Editing Antibiotic (section)

==== 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>