Editing Antibiotic (section)

==Antibiotic pipeline==
Both the WHO and the [[Infectious Disease Society of America]] report that the weak antibiotic pipeline does not match bacteria's increasing ability to develop resistance.<ref name="WHO - analysis of pipeline">Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis. Geneva: World Health Organization; 2017 (WHO/EMP/IAU/2017.12). Licence: CC BY-NC-SA 3.0 IGO.</ref><ref>{{cite journal | vauthors = Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D | title = 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 56 | issue = 12 | pages = 1685–94 | date = June 2013 | pmid = 23599308 | pmc = 3707426 | doi = 10.1093/cid/cit152 }}</ref> The Infectious Disease Society of America report noted that the number of new antibiotics approved for marketing per year had been declining and identified seven antibiotics against the [[Gram-negative bacilli]] currently in [[phases of clinical research#Phase II|phase 2]] or [[phases of clinical research#Phase III|phase 3]] clinical trials. However, these drugs did not address the entire spectrum of resistance of Gram-negative bacilli.<ref>{{cite news |title=Drug pipeline for worst superbugs 'on life support': report |vauthors=Steenhuysen J |url=http://in.reuters.com/article/us-antibiotics-superbugs-idINBRE93H05520130418 |work=Reuters |date=18 April 2013 |access-date=23 June 2013 |archive-date=25 December 2015 |archive-url=https://web.archive.org/web/20151225054947/http://in.reuters.com/article/us-antibiotics-superbugs-idINBRE93H05520130418 |url-status=dead }}</ref><ref name=IDSA2013>{{cite journal | vauthors = Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D | title = 10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 56 | issue = 12 | pages = 1685–94 | date = June 2013 | pmid = 23599308 | pmc = 3707426 | doi = 10.1093/cid/cit152 | others = Infectious Diseases Society of America }}</ref> According to the WHO fifty one new therapeutic entities - antibiotics (including combinations), are in phase 1–3 clinical trials as of May 2017.<ref name="WHO - analysis of pipeline"/> Antibiotics targeting multidrug-resistant Gram-positive pathogens remains a high priority.<ref>{{cite journal | vauthors = Liu J, Bedell TA, West JG, Sorensen EJ | title = Design and Synthesis of Molecular Scaffolds with Anti-infective Activity | journal = Tetrahedron | volume = 72 | issue = 25 | pages = 3579–3592 | date = June 2016 | pmid = 27284210 | pmc = 4894353 | doi = 10.1016/j.tet.2016.01.044 }}</ref><ref name="WHO - analysis of pipeline"/>

A few antibiotics have received marketing authorization in the last seven years. The cephalosporin ceftaroline and the lipoglycopeptides oritavancin and telavancin have been approved for the treatment of acute bacterial skin and skin structure infection and community-acquired bacterial pneumonia.<ref name="Fernandes, Martens">{{cite journal | vauthors = Fernandes P, Martens E | title = Antibiotics in late clinical development | journal = Biochemical Pharmacology | volume = 133 | pages = 152–163 | date = June 2017 | pmid = 27687641 | doi = 10.1016/j.bcp.2016.09.025 | doi-access = free | title-link = doi }}</ref> The lipoglycopeptide dalbavancin and the oxazolidinone tedizolid has also been approved for use for the treatment of acute bacterial skin and skin structure infection. The first in a new class of narrow-spectrum [[macrocycle|macrocyclic]] antibiotics, fidaxomicin, has been approved for the treatment of ''C. difficile'' colitis.<ref name="Fernandes, Martens"/> New cephalosporin-lactamase inhibitor combinations also approved include ceftazidime-avibactam and ceftolozane-avibactam for complicated urinary tract infection and intra-abdominal infection.<ref name="Fernandes, Martens"/>

{{Columns-list|colwidth=30em|
* [[Ceftolozane]]/[[tazobactam]] (CXA-201; CXA-101/tazobactam): [[Antipseudomonal]] [[cephalosporin]]/[[β-lactamase]] inhibitor combination (cell wall synthesis inhibitor). FDA approved on 19 December 2014.<ref>{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206829Orig1s000Approv.pdf|title=Approval Package for: application number: 206829Orig1s000|author=Center for Drug Evaluation and Research|date=19 December 2014|access-date=19 August 2024}}</ref>
* [[Ceftazidime]]/[[avibactam]] (ceftazidime/NXL104): antipseudomonal cephalosporin/β-lactamase inhibitor combination (cell wall synthesis inhibitor).<ref name="pmid32152527">{{cite journal | vauthors = Butler MS, Paterson DL | title = Antibiotics in the clinical pipeline in October 2019 | journal = The Journal of Antibiotics | volume = 73 | issue = 6 | pages = 329–364 | date = June 2020 | pmid = 32152527 | pmc = 7223789 | doi = 10.1038/s41429-020-0291-8 }}</ref> FDA approved on 25 February 2015.
* [[Ceftaroline]]/avibactam (CPT-avibactam; ceftaroline/NXL104): Anti-[[MRSA]] cephalosporin/ β-lactamase inhibitor combination (cell wall synthesis inhibitor).{{cn|date=August 2024}}
* [[Cefiderocol]]: [[cephalosporin]] siderophore.<ref name="pmid32152527"/> FDA approved on 14 November 2019.
* [[Imipenem]]/relebactam: [[carbapenem]]/ β-lactamase inhibitor combination (cell wall synthesis inhibitor).<ref name="pmid32152527"/> FDA approved on 16 July 2019.
* [[Meropenem/vaborbactam]]: [[carbapenem]]/ β-lactamase inhibitor combination (cell wall synthesis inhibitor).<ref name="pmid32152527"/> FDA approved on 29 August 2017.
* [[Delafloxacin]]: [[quinolone antibiotic|quinolone]] (inhibitor of DNA synthesis).<ref name="pmid32152527"/> FDA approved on 19 June 2017.
* [[Plazomicin]] (ACHN-490): semi-synthetic [[aminoglycoside]] derivative ([[protein synthesis inhibitor]]).<ref name="pmid32152527"/> FDA approved 25 June 2018.
* [[Eravacycline]] (TP-434): synthetic [[tetracycline]] derivative (protein synthesis inhibitor targeting bacterial ribosomes).<ref name="pmid32152527"/> FDA approved on 27 August 2018.
* [[Omadacycline]]: semi-synthetic [[tetracycline]] derivative (protein synthesis inhibitor targeting bacterial ribosomes).<ref name="pmid32152527"/> FDA approved on 2 October 2018.
* [[Lefamulin]]: pleuromutilin antibiotic.<ref name="pmid32152527"/> FDA approved on 19 August 2019.
* [[Brilacidin]] (PMX-30063): peptide defense protein mimetic (cell membrane disruption). In phase 2.<ref name="r165">{{cite journal | last=Nawrot | first=Daria | last2=Ambrożkiewicz-Mosler | first2=Weronika | last3=Doležal | first3=Martin | last4=Bouz | first4=Ghada | title=Antistaphylococcal discovery pipeline; where are we now? | journal=European Journal of Medicinal Chemistry | publisher=Elsevier BV | volume=266 | year=2024 | issn=0223-5234 | doi=10.1016/j.ejmech.2023.116077 | page=116077}}</ref>
* [[Zosurabalpin]] (RG-6006): lipopolysaccharide transport inhibitor. In phase 1.<ref>{{cite journal |last1=Zampaloni |first1=C |last2=Mattei |first2=P |last3=Bleicher |first3=K |last4=Winther |first4=L |last5=Thäte |first5=C |last6=Bucher |first6=C |last7=Adam |first7=JM |last8=Alanine |first8=A |last9=Amrein |first9=KE |last10=Baidin |first10=V |last11=Bieniossek |first11=C |last12=Bissantz |first12=C |last13=Boess |first13=F |last14=Cantrill |first14=C |last15=Clairfeuille |first15=T |last16=Dey |first16=F |last17=Di Giorgio |first17=P |last18=du Castel |first18=P |last19=Dylus |first19=D |last20=Dzygiel |first20=P |last21=Felici |first21=A |last22=García-Alcalde |first22=F |last23=Haldimann |first23=A |last24=Leipner |first24=M |last25=Leyn |first25=S |last26=Louvel |first26=S |last27=Misson |first27=P |last28=Osterman |first28=A |last29=Pahil |first29=K |last30=Rigo |first30=S |last31=Schäublin |first31=A |last32=Scharf |first32=S |last33=Schmitz |first33=P |last34=Stoll |first34=T |last35=Trauner |first35=A |last36=Zoffmann |first36=S |last37=Kahne |first37=D |last38=Young |first38=JAT |last39=Lobritz |first39=MA |last40=Bradley |first40=KA |title=A novel antibiotic class targeting the lipopolysaccharide transporter. |journal=Nature |date=3 January 2024 |volume=625 |issue=7995 |pages=566–571 |doi=10.1038/s41586-023-06873-0 |pmid=38172634| doi-access = free | title-link = doi |pmc=10794144 |bibcode=2024Natur.625..566Z }}</ref><ref>{{cite journal |last1=Pahil |first1=KS |last2=Gilman |first2=MSA |last3=Baidin |first3=V |last4=Clairfeuille |first4=T |last5=Mattei |first5=P |last6=Bieniossek |first6=C |last7=Dey |first7=F |last8=Muri |first8=D |last9=Baettig |first9=R |last10=Lobritz |first10=M |last11=Bradley |first11=K |last12=Kruse |first12=AC |last13=Kahne |first13=D |title=A new antibiotic traps lipopolysaccharide in its intermembrane transporter. |journal=Nature |date=3 January 2024 |volume=625 |issue=7995 |pages=572–577 |doi=10.1038/s41586-023-06799-7 |pmid=38172635| doi-access = free | title-link = doi |pmc=10794137 |bibcode=2024Natur.625..572P }}</ref>}}

Possible improvements include clarification of clinical trial regulations by FDA. Furthermore, appropriate economic incentives could persuade pharmaceutical companies to invest in this endeavor.<ref name="IDSA2013"/> In the US, the [[Antibiotic Development to Advance Patient Treatment]] (ADAPT) Act was introduced with the aim of fast tracking the [[drug development]] of antibiotics to combat the growing threat of 'superbugs'. Under this Act, FDA can approve antibiotics and antifungals treating life-threatening infections based on smaller clinical trials. The [[Centers for Disease Control and Prevention|CDC]] will monitor the use of antibiotics and the emerging resistance, and publish the data. The FDA antibiotics labeling process, 'Susceptibility Test Interpretive Criteria for Microbial Organisms' or 'breakpoints', will provide accurate data to healthcare professionals.<ref>{{cite web|url=http://assets.fiercemarkets.net/public/lifesciences/HR3742.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://assets.fiercemarkets.net/public/lifesciences/HR3742.pdf |archive-date=9 October 2022 |url-status=live|title=Antibiotic Development to Advance Patient Treatment Act of 2013|publisher=US Congress|date=12 December 2013}}</ref> According to Allan Coukell, senior director for health programs at The Pew Charitable Trusts, "By allowing drug developers to rely on smaller datasets, and clarifying FDA's authority to tolerate a higher level of uncertainty for these drugs when making a risk/benefit calculation, ADAPT would make the clinical trials more feasible."<ref>{{cite news|vauthors=Clarke T|title=U.S. Congress urged to pass bill to speed development of antibiotics|url=https://www.reuters.com/article/us-usa-congress-antibiotics-idUSKBN0HE25W20140919|agency=Reuters|access-date=19 September 2014|newspaper=Reuters|date=19 September 2014|archive-date=9 December 2015|archive-url=https://web.archive.org/web/20151209012151/http://www.reuters.com/article/us-usa-congress-antibiotics-idUSKBN0HE25W20140919|url-status=live}}</ref>

=== Replenishing the antibiotic pipeline and developing other new therapies ===
Because antibiotic-resistant bacterial strains continue to emerge and spread, there is a constant need to develop new antibacterial treatments. Current strategies include traditional chemistry-based approaches such as [[natural product]]-based [[drug discovery]],<ref name="Natural Products">{{cite journal | vauthors = Moloney MG | title = Natural Products as a Source for Novel Antibiotics | journal = Trends in Pharmacological Sciences | volume = 37 | issue = 8 | pages = 689–701 | date = August 2016 | pmid = 27267698 | doi = 10.1016/j.tips.2016.05.001 | s2cid = 3537191 | url = https://ora.ox.ac.uk/objects/uuid:53d851f3-3719-4ac3-aa5a-b70ac82e4115 | access-date = 25 August 2020 | archive-date = 27 July 2021 | archive-url = https://web.archive.org/web/20210727100821/https://ora.ox.ac.uk/objects/uuid:53d851f3-3719-4ac3-aa5a-b70ac82e4115 | url-status = live }}</ref><ref name="pmid32529587">{{cite journal | vauthors = Cushnie TP, Cushnie B, Echeverría J, Fowsantear W, Thammawat S, Dodgson JL, Law S, Clow SM | title = Bioprospecting for Antibacterial Drugs: a Multidisciplinary Perspective on Natural Product Source Material, Bioassay Selection and Avoidable Pitfalls | journal = Pharmaceutical Research | volume = 37 | issue = 7 | pages = 125 | date = June 2020 | pmid = 32529587 | doi = 10.1007/s11095-020-02849-1 | url = https://zenodo.org/record/3909383 | s2cid = 219590658 | access-date = 17 September 2020 | archive-date = 2 December 2020 | archive-url = https://web.archive.org/web/20201202010902/https://zenodo.org/record/3909383 | url-status = live }}</ref> newer chemistry-based approaches such as [[drug design]],<ref name="pmid32199982">{{cite journal | vauthors = Mashalidis EH, Lee SY | title = Structures of Bacterial MraY and Human GPT Provide Insights into Rational Antibiotic Design | journal = Journal of Molecular Biology | volume = 432 | issue = 18 | pages = 4946–4963 | date = August 2020 | pmid = 32199982 | doi = 10.1016/j.jmb.2020.03.017 | pmc = 8351759 }}</ref><ref name="pmid30360704">{{cite journal | vauthors = Xia J, Feng B, Wen G, Xue W, Ma G, Zhang H, Wu S | title = Bacterial Lipoprotein Biosynthetic Pathway as a Potential Target for Structure-based Design of Antibacterial Agents | journal = Current Medicinal Chemistry | volume = 27 | issue = 7 | pages = 1132–1150 | date = July 2020 | pmid = 30360704 | doi = 10.2174/0929867325666181008143411 | s2cid = 53097836 }}</ref> traditional biology-based approaches such as [[immunoglobulin therapy]],<ref name="pmid31295426"/><ref name="pmid30683453"/> and experimental biology-based approaches such as [[phage therapy]],<ref>{{cite journal | vauthors = Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM | title = Phage treatment of human infections | journal = Bacteriophage | volume = 1 | issue = 2 | pages = 66–85 | date = March 2011 | pmid = 22334863 | pmc = 3278644 | doi = 10.4161/bact.1.2.15845 }}</ref><ref name="pmid26795692">{{cite journal | vauthors = Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H, Fischetti VA, Foster S, Gilmore BF, Hancock RE, Harper D, Henderson IR, Hilpert K, Jones BV, Kadioglu A, Knowles D, Ólafsdóttir S, Payne D, Projan S, Shaunak S, Silverman J, Thomas CM, Trust TJ, Warn P, Rex JH | title = Alternatives to antibiotics-a pipeline portfolio review | journal = The Lancet. Infectious Diseases | volume = 16 | issue = 2 | pages = 239–51 | date = February 2016 | pmid = 26795692 | doi = 10.1016/S1473-3099(15)00466-1 | s2cid = 21677232 | url = http://eprints.brighton.ac.uk/14828/1/Alternatives%20to%20Antibiotics%20-%20a%20pipeline%20portfolio%20review.pdf | access-date = 22 November 2018 | archive-date = 17 August 2019 | archive-url = https://web.archive.org/web/20190817222112/http://eprints.brighton.ac.uk/14828/1/Alternatives%20to%20Antibiotics%20-%20a%20pipeline%20portfolio%20review.pdf | url-status = live }}</ref> [[fecal microbiota transplant]]s,<ref name="pmid31295426"/><ref>{{cite journal | vauthors = Moayyedi P, Yuan Y, Baharith H, Ford AC | title = Faecal microbiota transplantation for ''Clostridium difficile''-associated diarrhoea: a systematic review of randomised controlled trials | journal = The Medical Journal of Australia | volume = 207 | issue = 4 | pages = 166–172 | date = August 2017 | pmid = 28814204 | doi = 10.5694/mja17.00295 | s2cid = 24780848 }}</ref> [[antisense RNA]]-based treatments,<ref name="pmid31295426"/><ref name="pmid30683453"/> and [[CRISPR|CRISPR-Cas9]]-based treatments.<ref name="pmid31295426"/><ref name="pmid30683453">{{cite journal | vauthors = Ghosh C, Sarkar P, Issa R, Haldar J | title = Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance | journal = Trends in Microbiology | volume = 27 | issue = 4 | pages = 323–338 | date = April 2019 | pmid = 30683453 | doi = 10.1016/j.tim.2018.12.010 | s2cid = 59274650}}</ref><ref name="pmid32575913">{{cite journal | vauthors = Vrancianu CO, Gheorghe I, Czobor IB, Chifiriuc MC | title = Antibiotic Resistance Profiles, Molecular Mechanisms and Innovative Treatment Strategies of ''Acinetobacter baumannii'' | journal = Microorganisms | volume = 8 | issue = 6 | pages = Article 935 | date = June 2020 | pmid = 32575913 | pmc = 7355832 | doi = 10.3390/microorganisms8060935 | doi-access = free | title-link = doi }}</ref>

==== Natural product-based antibiotic discovery ====
{{See also|Bioprospecting}}
{{multiple image|perrow = 2|total_width=275| image1 = Streptomyces sp 01.png| image2 = Acremonium falciforme PHIL 4167 lores.jpg| image3 = Hydrastis.jpg| image4 = Agelas tubulata cropped.jpg|footer = Bacteria, fungi, plants, animals and other organisms are being screened in the search for new antibiotics.<ref name="pmid32529587"/>}}
Most of the antibiotics in current use are [[natural product]]s or natural product derivatives,<ref name="pmid32529587"/><ref name="pmid31733401">{{cite journal | vauthors = Hutchings MI, Truman AW, Wilkinson B | title = Antibiotics: past, present and future | journal = Current Opinion in Microbiology | volume = 51 | pages = 72–80 | date = October 2019 | pmid = 31733401 | doi = 10.1016/j.mib.2019.10.008 | doi-access = free | title-link = doi }}</ref> and [[bacteria]]l,<ref>{{cite journal | vauthors = Holmes NA, Devine R, Qin Z, Seipke RF, Wilkinson B, Hutchings MI | title = Complete genome sequence of Streptomyces formicae KY5, the formicamycin producer | journal = Journal of Biotechnology | volume = 265 | pages = 116–118 | date = January 2018 | pmid = 29191667 | doi = 10.1016/j.jbiotec.2017.11.011 | doi-access = free | title-link = doi }}</ref><ref>{{Cite web|url=http://www.hutchingslab.uk/papers.html|title=Recent Papers (2012-2015)|website=www.hutchingslab.uk|access-date=22 August 2022|archive-date=2 October 2015|archive-url=https://web.archive.org/web/20151002042551/http://www.hutchingslab.uk/papers.html|url-status=usurped}}</ref> [[fungal]],<ref name="Natural Products "/><ref name="pmid23978412">{{cite journal | vauthors = Bills GF, Gloer JB, An Z | title = Coprophilous fungi: antibiotic discovery and functions in an underexplored arena of microbial defensive mutualism | journal = Current Opinion in Microbiology | volume = 16 | issue = 5 | pages = 549–65 | date = October 2013 | pmid = 23978412 | doi = 10.1016/j.mib.2013.08.001 }}</ref> [[plant]]<ref name="Kenny, Furey, Lucey">{{cite journal | vauthors = Kenny CR, Furey A, Lucey B | title = A post-antibiotic era looms: can plant natural product research fill the void? | journal = British Journal of Biomedical Science | volume = 72 | issue = 4 | pages = 191–200 | year = 2015 | pmid = 26738402 | doi = 10.1080/09674845.2015.11665752 | s2cid = 41282022 }}</ref><ref>{{cite journal | vauthors = Al-Habib A, Al-Saleh E, Safer AM, Afzal M | title = Bactericidal effect of grape seed extract on methicillin-resistant Staphylococcus aureus (MRSA) | journal = The Journal of Toxicological Sciences | volume = 35 | issue = 3 | pages = 357–64 | date = June 2010 | pmid = 20519844 | doi = 10.2131/jts.35.357 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Smullen J, Koutsou GA, Foster HA, Zumbé A, Storey DM | title = The antibacterial activity of plant extracts containing polyphenols against Streptococcus mutans | journal = Caries Research | volume = 41 | issue = 5 | pages = 342–9 | year = 2007 | pmid = 17713333 | doi = 10.1159/000104791 | s2cid = 44317367 }}</ref><ref name="Monte">{{cite journal | vauthors = Monte J, Abreu AC, Borges A, Simões LC, Simões M | title = Antimicrobial Activity of Selected Phytochemicals against Escherichia coli and Staphylococcus aureus and Their Biofilms | journal = Pathogens | volume = 3 | issue = 2 | pages = 473–98 | date = June 2014 | pmid = 25437810 | pmc = 4243457 | doi = 10.3390/pathogens3020473 | doi-access = free | title-link = doi }}</ref> and [[animal]]<ref name="Natural Products"/><ref name="pmid27373625 ">{{cite journal | vauthors = Tanaka N, Kusama T, Kashiwada Y, Kobayashi J | title = Bromopyrrole Alkaloids from Okinawan Marine Sponges Agelas spp | journal = Chemical & Pharmaceutical Bulletin | volume = 64 | issue = 7 | pages = 691–4 | date = April 2016 | pmid = 27373625 | doi = 10.1248/cpb.c16-00245 | doi-access = free | title-link = doi }}</ref> extracts are being screened in the search for new antibiotics. Organisms may be selected for testing based on [[ecological]], [[ethnomedical]], [[genomic]], or [[historical]] rationales.<ref name="pmid32529587"/> [[Medicinal plants]], for example, are screened on the basis that they are used by traditional healers to prevent or cure infection and may therefore contain antibacterial compounds.<ref name="cowen">{{cite journal | vauthors = Cowan MM | title = Plant products as antimicrobial agents | journal = Clinical Microbiology Reviews | volume = 12 | issue = 4 | pages = 564–82 | date = October 1999 | pmid = 10515903 | pmc = 88925 | doi = 10.1128/CMR.12.4.564 }}</ref><ref name=" Plants as sources"/> Also, soil bacteria are screened on the basis that, historically, they have been a very rich source of antibiotics (with 70 to 80% of antibiotics in current use derived from the [[actinomycetes]]).<ref name="pmid32529587"/><ref name="pmid27890726 ">{{cite journal | vauthors = Mahajan GB, Balachandran L | title = Sources of antibiotics: Hot springs | journal = Biochemical Pharmacology | volume = 134 | pages = 35–41 | date = June 2017 | pmid = 27890726 | doi = 10.1016/j.bcp.2016.11.021 }}</ref>

In addition to screening natural products for direct antibacterial activity, they are sometimes screened for the ability to suppress [[antimicrobial resistance|antibiotic resistance]] and [[antibiotic tolerance]].<ref name="Plants as sources">{{cite journal | vauthors = Abreu AC, McBain AJ, Simões M | title = Plants as sources of new antimicrobials and resistance-modifying agents | journal = Natural Product Reports | volume = 29 | issue = 9 | pages = 1007–21 | date = September 2012 | pmid = 22786554 | doi = 10.1039/c2np20035j }}</ref><ref name="pmid21562562"/> For example, some [[secondary metabolites]] inhibit [[drug efflux]] pumps, thereby increasing the concentration of antibiotic able to reach its cellular target and decreasing bacterial resistance to the antibiotic.<ref name="Plants as sources"/><ref name="Efflux pump inhibitors">{{cite journal | vauthors = Marquez B | title = Bacterial efflux systems and efflux pumps inhibitors | journal = Biochimie | volume = 87 | issue = 12 | pages = 1137–47 | date = December 2005 | pmid = 15951096 | doi = 10.1016/j.biochi.2005.04.012 }}</ref> Natural products known to inhibit bacterial efflux pumps include the [[alkaloid]] [[lysergol]],<ref>{{cite journal | vauthors = Cushnie TP, Cushnie B, Lamb AJ | title = Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities | journal = International Journal of Antimicrobial Agents | volume = 44 | issue = 5 | pages = 377–86 | date = November 2014 | pmid = 25130096 | doi = 10.1016/j.ijantimicag.2014.06.001 | s2cid = 205171789 | url = https://zenodo.org/record/1004771 | access-date = 19 July 2019 | archive-date = 18 August 2020 | archive-url = https://web.archive.org/web/20200818103721/https://zenodo.org/record/1004771 | url-status = live }}</ref> the [[carotenoid]]s [[capsanthin]] and [[capsorubin]],<ref name="pmid20645919">{{cite journal | vauthors = Molnár J, Engi H, Hohmann J, Molnár P, Deli J, Wesolowska O, Michalak K, Wang Q | title = Reversal of multidrug resistance by natural substances from plants | journal = Current Topics in Medicinal Chemistry | volume = 10 | issue = 17 | pages = 1757–68 | year = 2010 | pmid = 20645919 | doi = 10.2174/156802610792928103 }}</ref> and the [[flavonoid]]s [[rotenone]] and [[chrysin]].<ref name="pmid20645919" /> Other natural products, this time [[primary metabolite]]s rather than secondary metabolites, have been shown to eradicate antibiotic tolerance. For example, [[glucose]], [[mannitol]], and [[fructose]] reduce antibiotic tolerance in ''[[Escherichia coli]]'' and ''[[Staphylococcus aureus]]'', rendering them more susceptible to killing by [[aminoglycoside]] antibiotics.<ref name="pmid21562562">{{cite journal | vauthors = Allison KR, Brynildsen MP, Collins JJ | title = Metabolite-enabled eradication of bacterial persisters by aminoglycosides | journal = Nature | volume = 473 | issue = 7346 | pages = 216–20 | date = May 2011 | pmid = 21562562 | pmc = 3145328 | doi = 10.1038/nature10069 | bibcode = 2011Natur.473..216A }}</ref>

Natural products may be screened for the ability to suppress bacterial [[virulence factor]]s too. Virulence factors are molecules, cellular structures and regulatory systems that enable bacteria to evade the body's immune defenses (e.g. [[urease]], [[staphyloxanthin]]), move towards, attach to, and/or invade human cells (e.g. [[type IV pili]], [[Bacterial adhesin|adhesin]]s, [[internalin]]s), coordinate the activation of virulence genes (e.g. [[quorum sensing]]), and cause disease (e.g. [[exotoxin]]s).<ref name="pmid31295426 ">{{cite journal | vauthors = Theuretzbacher U, Piddock LJ | title = Non-traditional Antibacterial Therapeutic Options and Challenges | journal = Cell Host & Microbe | volume = 26 | issue = 1 | pages = 61–72 | date = July 2019 | pmid = 31295426 | doi = 10.1016/j.chom.2019.06.004 | doi-access = free | title-link = doi }}</ref><ref name="Monte"/><ref name="pmid21514796">{{cite journal | vauthors = Cushnie TP, Lamb AJ | title = Recent advances in understanding the antibacterial properties of flavonoids | journal = International Journal of Antimicrobial Agents | volume = 38 | issue = 2 | pages = 99–107 | date = August 2011 | pmid = 21514796 | doi = 10.1016/j.ijantimicag.2011.02.014 | url = https://zenodo.org/record/1003263 | access-date = 19 July 2019 | archive-date = 26 July 2020 | archive-url = https://web.archive.org/web/20200726062743/https://zenodo.org/record/1003263 | url-status = live }}</ref><ref name="pmid31410034"/><ref>{{cite journal | vauthors = Mok N, Chan SY, Liu SY, Chua SL | title = Vanillin inhibits PqsR-mediated virulence in Pseudomonas aeruginosa | journal = Food & Function | volume = 11 | issue = 7 | pages = 6496–6508 | date = July 2020 | pmid = 32697213 | doi = 10.1039/D0FO00046A | hdl = 10397/88306 | s2cid = 220699939 | hdl-access = free }}</ref> Examples of natural products with antivirulence activity include the flavonoid [[epigallocatechin gallate]] (which inhibits [[listeriolysin O]]),<ref name="pmid21514796"/> the [[quinone]] tetrangomycin (which inhibits staphyloxanthin),<ref name="pmid31410034">{{cite journal | vauthors = Xue L, Chen YY, Yan Z, Lu W, Wan D, Zhu H | title = Staphyloxanthin: a potential target for antivirulence therapy | journal = Infection and Drug Resistance | volume = 12 | pages = 2151–2160 | date = July 2019 | pmid = 31410034 | pmc = 6647007 | doi = 10.2147/IDR.S193649 | doi-access = free | title-link = doi }}</ref> and the [[sesquiterpene]] zerumbone (which inhibits ''[[Acinetobacter baumannii]]'' [[Bacteria#Movement|motility]]).<ref name="pmid32463353">{{cite journal | vauthors = Kim HR, Shin DS, Jang HI, Eom YB | title = Anti-biofilm and anti-virulence effects of zerumbone against ''Acinetobacter baumannii'' | journal = Microbiology | volume = 166 | issue = 8 | pages = 717–726 | date = August 2020 | pmid = 32463353 | doi = 10.1099/mic.0.000930 | doi-access = free | title-link = doi }}</ref>

==== Immunoglobulin therapy ====
{{Main|Monoclonal antibody therapy}}
Antibodies ([[anti-tetanus immunoglobulin]]) have been used in the treatment and prevention of [[tetanus]] since the 1910s,<ref>{{cite book| vauthors = Plotkin SA, Orenstein WA, Offit PA |author-link2=Walter Orenstein |author-link1=Stanley Plotkin |author-link3=Paul Offit|title=Vaccines|date=2012|publisher=Elsevier Health Sciences|isbn=978-1-4557-0090-5|pages=103, 757|url=https://books.google.com/books?id=hoigDQ6vdDQC&pg=PA103|language=en|url-status=live|archive-url=https://web.archive.org/web/20170109021821/https://books.google.ca/books?id=hoigDQ6vdDQC&pg=PA103|archive-date=9 January 2017}}</ref> and this approach continues to be a useful way of controlling bacterial diseases. The [[monoclonal antibody]] [[bezlotoxumab]], for example, has been approved by the [[Food and Drug Administration|US FDA]] and [[European Medicines Agency|EMA]] for recurrent [[Clostridioides difficile infection]], and other monoclonal antibodies are in development (e.g. AR-301 for the adjunctive treatment of ''S. aureus'' [[ventilator-associated pneumonia]]). Antibody treatments act by binding to and neutralizing bacterial exotoxins and other virulence factors.<ref name="pmid31295426"/><ref name="pmid30683453"/>

==== Phage therapy ====
{{Main|Phage therapy}}
[[Image: Phage injecting its genome into bacteria.svg|thumb|upright=0.74|right| Phage injecting its genome into a bacterium. Viral replication and bacterial cell lysis will ensue.<ref name=Sulakvelidze/>]]
[[Phage therapy]] is under investigation as a method of treating antibiotic-resistant strains of bacteria. Phage therapy involves infecting bacterial pathogens with [[virus]]es. [[Bacteriophage]]s and their host ranges are extremely specific for certain bacteria, thus, unlike antibiotics, they do not disturb the host organism's [[intestinal microbiota]].<ref name="Gill, Franco, Hancock"/> Bacteriophages, also known as phages, infect and kill bacteria primarily during lytic cycles.<ref name="Gill, Franco, Hancock"/><ref name=Sulakvelidze>{{cite journal | vauthors = Sulakvelidze A, Alavidze Z, Morris JG | title = Bacteriophage therapy | journal = Antimicrobial Agents and Chemotherapy | volume = 45 | issue = 3 | pages = 649–59 | date = March 2001 | pmid = 11181338 | pmc = 90351 | doi = 10.1128/aac.45.3.649-659.2001 }}</ref> Phages insert their DNA into the bacterium, where it is transcribed and used to make new phages, after which the cell will lyse, releasing new phage that are able to infect and destroy further bacteria of the same strain.<ref name=Sulakvelidze/> The high specificity of phage protects [[Mutualism (biology)|"good"]] bacteria from destruction.<ref>{{cite journal | vauthors = Dunne M, Rupf B, Tala M, Qabrati X, Ernst P, Shen Y, Sumrall E, Heeb L, Plückthun A, Loessner MJ, Kilcher S | title = Reprogramming Bacteriophage Host Range through Structure-Guided Design of Chimeric Receptor Binding Proteins | journal = Cell Reports | volume = 29 | issue = 5 | pages = 1336–1350.e4 | date = October 2019 | pmid = 31665644 | s2cid = 204967212 | doi = 10.1016/j.celrep.2019.09.062 | doi-access = free | title-link = doi | hdl = 20.500.11850/374453 | hdl-access = free }}</ref>

Some disadvantages to the use of bacteriophages also exist, however. Bacteriophages may harbour virulence factors or toxic genes in their genomes and, prior to use, it may be prudent to identify genes with similarity to known virulence factors or toxins by genomic sequencing. In addition, the oral and [[intravenous|IV]] administration of phages for the eradication of bacterial infections poses a much higher safety risk than topical application. Also, there is the additional concern of uncertain immune responses to these large antigenic cocktails.{{citation needed|date=January 2021}}

There are considerable [[Regulation of therapeutic goods|regulatory]] hurdles that must be cleared for such therapies.<ref name="Gill, Franco, Hancock">{{cite journal | vauthors = Gill EE, Franco OL, Hancock RE | title = Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens | journal = Chemical Biology & Drug Design | volume = 85 | issue = 1 | pages = 56–78 | date = January 2015 | pmid = 25393203 | pmc = 4279029 | doi = 10.1111/cbdd.12478 }}</ref> Despite numerous challenges, the use of bacteriophages as a replacement for antimicrobial agents against MDR pathogens that no longer respond to conventional antibiotics, remains an attractive option.<ref name="Gill, Franco, Hancock"/><ref>{{cite journal | vauthors = Opal SM | title = Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance | journal = Critical Care | volume = 20 | issue = 1 | pages = 397 | date = December 2016 | pmid = 27978847 | pmc = 5159963 | doi = 10.1186/s13054-016-1549-1 | doi-access = free | title-link = doi }}</ref>

==== Fecal microbiota transplants ====
{{Main| Fecal microbiota transplant }}
[[Image: E coli at 10000x, original.jpg|thumb|upright=0.74|right|Fecal microbiota transplants are an experimental treatment for ''C. difficile'' infection.<ref name="pmid31295426"/>]]
Fecal microbiota transplants involve transferring the full [[intestinal microbiota]] from a healthy human donor (in the form of [[feces|stool]]) to patients with [[Clostridioides difficile infection|''C. difficile'' infection]]. Although this procedure has not been officially approved by the [[Food and Drug Administration|US FDA]], its use is permitted under some conditions in patients with antibiotic-resistant ''C. difficile'' infection. Cure rates are around 90%, and work is underway to develop stool [[biobank|banks]], standardized products, and methods of [[Oral administration|oral delivery]].<ref name="pmid31295426"/> Fecal microbiota transplantation has also been used more recently for inflammatory bowel diseases.<ref>{{cite journal | vauthors = D'Odorico I, Di Bella S, Monticelli J, Giacobbe DR, Boldock E, Luzzati R | title = Role of fecal microbiota transplantation in inflammatory bowel disease | journal = Journal of Digestive Diseases | volume = 19 | issue = 6 | pages = 322–334 | date = June 2018 | pmid = 29696802 | doi = 10.1111/1751-2980.12603 | s2cid = 24461869 }}</ref>

==== Antisense RNA-based treatments ====
{{See|Antisense RNA}}
Antisense RNA-based treatment (also known as gene silencing therapy) involves (a) identifying bacterial [[gene]]s that encode essential [[protein]]s (e.g. the ''[[Pseudomonas aeruginosa]]'' genes ''acpP'', ''lpxC'', and ''rpsJ''), (b) synthesizing single-stranded [[RNA]] that is complementary to the [[messenger RNA|mRNA]] encoding these essential proteins, and (c) delivering the single-stranded RNA to the infection site using cell-penetrating peptides or [[liposome]]s. The antisense RNA then [[Nucleic acid hybridization|hybridizes]] with the bacterial mRNA and blocks its [[Translation (biology)|translation]] into the essential protein. Antisense RNA-based treatment has been shown to be effective in ''in vivo'' models of ''P. aeruginosa'' [[lung infection|pneumonia]].<ref name="pmid31295426"/><ref name="pmid30683453"/>

In addition to silencing essential bacterial genes, antisense RNA can be used to silence bacterial genes responsible for antibiotic resistance.<ref name="pmid31295426"/><ref name="pmid30683453"/> For example, antisense RNA has been developed that silences the ''S. aureus'' ''[[mecA]]'' gene (the gene that encodes modified [[penicillin-binding protein]] 2a and renders ''S. aureus'' strains [[Methicillin-resistant Staphylococcus aureus|methicillin-resistant]]). Antisense RNA targeting ''mecA'' mRNA has been shown to restore the susceptibility of methicillin-resistant staphylococci to [[oxacillin]] in both ''in vitro'' and ''in vivo'' studies.<ref name="pmid30683453"/>

==== CRISPR-Cas9-based treatments ====
In the early 2000s, a system was discovered that enables bacteria to defend themselves against invading viruses. The system, known as CRISPR-Cas9, consists of (a) an enzyme that destroys DNA (the [[nuclease]] [[Cas9]]) and (b) the DNA sequences of previously encountered viral invaders ([[CRISPR]]). These viral DNA sequences enable the nuclease to target foreign (viral) rather than self (bacterial) DNA.<ref name="pmid29358495">{{cite journal | vauthors = Ishino Y, Krupovic M, Forterre P | title = History of CRISPR-Cas from Encounter with a Mysterious Repeated Sequence to Genome Editing Technology | journal = Journal of Bacteriology | volume = 200 | issue = 7 | pages = e00580-17 | date = April 2018 | pmid = 29358495 | pmc = 5847661 | doi = 10.1128/JB.00580-17 }}</ref>

Although the function of CRISPR-Cas9 in nature is to protect bacteria, the DNA sequences in the CRISPR component of the system can be modified so that the Cas9 nuclease targets bacterial [[antimicrobial resistance|resistance]] genes or bacterial [[virulence]] genes instead of viral genes. The modified CRISPR-Cas9 system can then be administered to bacterial pathogens using plasmids or bacteriophages.<ref name="pmid31295426"/><ref name="pmid30683453"/> This approach has successfully been used to [[Gene silencing|silence]] antibiotic resistance and reduce the virulence of [[Shigatoxigenic and verotoxigenic Escherichia coli|enterohemorrhagic ''E. coli'']] in an ''in vivo'' model of infection.<ref name="pmid30683453"/>

=== Reducing the selection pressure for antibiotic resistance ===
{{Main|Antimicrobial resistance}}
[[Image:Share of population using safely managed sanitation facilities, OWID.svg|thumb|right|300px| Share of population using safely managed sanitation facilities in 2022<ref>Ritchie, Roser, Mispy, Ortiz-Ospina (2018) [https://sdg-tracker.org/water-and-sanitation "Measuring progress towards the Sustainable Development Goals." (SDG 6)] {{Webarchive|url=https://web.archive.org/web/20201101050352/https://sdg-tracker.org/water-and-sanitation |date=1 November 2020 }} ''SDG-Tracker.org, website''</ref>]]
In addition to developing new antibacterial treatments, it is important to reduce the [[selection pressure]] for the emergence and spread of [[antimicrobial resistance]] (AMR), such as antibiotic resistance. Strategies to accomplish this include well-established infection control measures such as infrastructure improvement (e.g. less crowded housing),<ref>{{cite web |url= https://www.ncbi.nlm.nih.gov/books/NBK535289/ |title= Household crowding |publisher= World Health Organization |access-date= 17 September 2020 |archive-date= 6 January 2021 |archive-url= https://web.archive.org/web/20210106220730/https://www.ncbi.nlm.nih.gov/books/NBK535289/ |url-status= live }}</ref><ref name="pmid30545014">{{cite journal | vauthors = Ali SH, Foster T, Hall NL | title = The Relationship between Infectious Diseases and Housing Maintenance in Indigenous Australian Households | journal = International Journal of Environmental Research and Public Health | volume = 15 | issue = 12 | pages = Article 2827 | date = December 2018 | pmid = 30545014 | pmc = 6313733 | doi = 10.3390/ijerph15122827 | doi-access = free | title-link = doi }}</ref> better sanitation (e.g. safe drinking water and food),<ref>{{cite web|url= https://www.who.int/water_sanitation_health/publications/facts2004/en/|title= Water, sanitation and hygiene links to health|publisher= World Health Organization|access-date= 17 September 2020|archive-date= 7 September 2020|archive-url= https://web.archive.org/web/20200907205101/https://www.who.int/water_sanitation_health/publications/facts2004/en/|url-status= live}}</ref><ref name="pmid21453872">{{cite journal | vauthors = Curtis V, Schmidt W, Luby S, Florez R, Touré O, Biran A | title = Hygiene: new hopes, new horizons | journal = The Lancet. Infectious Diseases | volume = 11 | issue = 4 | pages = 312–21 | date = April 2011 | pmid = 21453872 | pmc = 7106354 | doi = 10.1016/S1473-3099(10)70224-3 }}</ref> better use of vaccines and [[Pipeline vaccine|vaccine development]],<ref name=WHO10October2024/><ref name=" pmid26795692"/> other approaches such as [[antibiotic stewardship]],<ref name="pmid31836329">{{cite journal | vauthors = Gentry EM, Kester S, Fischer K, Davidson LE, Passaretti CL | title = Bugs and Drugs: Collaboration Between Infection Prevention and Antibiotic Stewardship | journal = Infectious Disease Clinics of North America | volume = 34 | issue = 1 | pages = 17–30 | date = March 2020 | pmid = 31836329 | doi = 10.1016/j.idc.2019.10.001 | s2cid = 209358146 }}</ref><ref name="pmid31585470">{{cite journal | vauthors = Fierens J, Depuydt PO, De Waele JJ | title = A Practical Approach to Clinical Antibiotic Stewardship in the ICU Patient with Severe Infection | journal = Seminars in Respiratory and Critical Care Medicine | volume = 40 | issue = 4 | pages = 435–446 | date = August 2019 | pmid = 31585470 | doi = 10.1055/s-0039-1693995 | s2cid = 203720304 }}</ref> and experimental approaches such as the use of [[Prebiotic (nutrition)|prebiotics]] and [[probiotics]] to prevent infection.<ref name="pmid32800382">{{cite journal | vauthors = Newman AM, Arshad M | title = The Role of Probiotics, Prebiotics and Synbiotics in Combating Multidrug-Resistant Organisms | journal = Clinical Therapeutics | volume = 42 | issue = 9 | pages = 1637–1648 | date = September 2020 | pmid = 32800382 | pmc = 7904027 | doi = 10.1016/j.clinthera.2020.06.011 | doi-access = free | title-link = doi }}</ref><ref name="pmid31083597">{{cite journal | vauthors = Giordano M, Baldassarre ME, Palmieri V, Torres DD, Carbone V, Santangelo L, Gentile F, Panza R, Di Mauro F, Capozza M, Di Mauro A, Laforgia N | title = Management of STEC Gastroenteritis: Is There a Role for Probiotics? | journal = International Journal of Environmental Research and Public Health | volume = 16 | issue = 9 | pages = Article 1649 | date = May 2019 | pmid = 31083597 | pmc = 6539596 | doi = 10.3390/ijerph16091649 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Jha R, Das R, Oak S, Mishra P | title = Probiotics (Direct-Fed Microbials) in Poultry Nutrition and Their Effects on Nutrient Utilization, Growth and Laying Performance, and Gut Health: A Systematic Review | journal = Animals | volume = 10 | issue = 10 | pages = 1863 | date = October 2020 | pmid = 33066185 | pmc = 7602066 | doi = 10.3390/ani10101863 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Jha R, Mishra P | title = Dietary fiber in poultry nutrition and their effects on nutrient utilization, performance, gut health, and on the environment: a review | journal = Journal of Animal Science and Biotechnology | volume = 12 | issue = 1 | pages = 51 | date = April 2021 | pmid = 33866972 | pmc = 8054369 | doi = 10.1186/s40104-021-00576-0 | doi-access = free | title-link = doi }}</ref> Antibiotic cycling, where antibiotics are alternated by clinicians to treat microbial diseases, is proposed, but recent studies revealed such strategies are ineffective against antibiotic resistance.<ref>{{cite journal | vauthors = Beckley AM, Wright ES | title = Identification of antibiotic pairs that evade concurrent resistance via a retrospective analysis of antimicrobial susceptibility test results | language = English | journal = The Lancet. Microbe | volume = 2 | issue = 10 | pages = e545–e554 | date = October 2021 | pmid = 34632433 | pmc = 8496867 | doi = 10.1016/S2666-5247(21)00118-X }}</ref><ref>{{Cite journal| vauthors = Ma Y, Chua SL |date=15 November 2021|title=No collateral antibiotic sensitivity by alternating antibiotic pairs | journal=The Lancet Microbe|volume=3|issue=1 |pages=e7|language=English|doi=10.1016/S2666-5247(21)00270-6|pmid=35544116 |s2cid=244147577|issn=2666-5247| doi-access = free | title-link = doi }}</ref>

==== Vaccines ====

[[Vaccine]]s are an essential part of the response to reduce AMR as they prevent infections, reduce the use and overuse of antimicrobials, and slow the emergence and spread of drug-resistant pathogens.<ref name=WHO10October2024/> Vaccination either excites or reinforces the immune competence of a host to ward off infection, leading to the activation of [[macrophages]], the production of [[antibody|antibodies]], [[inflammation]], and other classic immune reactions. Antibacterial vaccines have been responsible for a drastic reduction in global bacterial diseases.<ref>{{cite book |title= Emerging trends in antibacterial discovery: answering the call to arms |publisher= Horizon Scientific Press |year= 2011 | vauthors = Donald RG, Anderson AS | veditors = Miller PF |chapter= Current strategies for antibacterial vaccine development |page= 283}}</ref>