Editing Antimicrobial resistance (section)

===Development of new drugs===
Since the discovery of antibiotics, [[research and development]] (R&D) efforts have provided new drugs in time to treat bacteria that became resistant to older antibiotics, but in the 2000s there has been concern that development has slowed enough that seriously ill people may run out of treatment options.<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>{{cite web |url= https://www.wp.dh.gov.uk/publications/files/2013/03/CMO-Annual-Report-Volume-2-20111.pdf |title=Annual Report of the Chief Medical Officer - Infections and the rise of antimicrobial resistance|date=2011|publisher=UK NHS|archive-url=https://web.archive.org/web/20131030190650/http://media.dh.gov.uk/network/357/files/2013/03/CMO-Annual-Report-Volume-2-20111.pdf|archive-date=30 October 2013|url-status=dead}}</ref> Another concern is that practitioners may become reluctant to perform routine surgeries because of the increased risk of harmful infection.<ref name="obama">{{cite news|url=https://www.npr.org/blogs/health/2013/06/04/188380562/obama-administration-seeks-to-loosen-antibiotic-approvals|title=Obama Administration Seeks To Ease Approvals For Antibiotics|newspaper=NPR.org|date=4 June 2013|publisher=NPR|access-date=7 August 2016|archive-url=https://web.archive.org/web/20150313042023/http://www.npr.org/blogs/health/2013/06/04/188380562/obama-administration-seeks-to-loosen-antibiotic-approvals|archive-date=13 March 2015|url-status=live}}</ref> Backup treatments can have serious side-effects; for example, antibiotics like [[aminoglycoside]]s (such as [[amikacin]], [[gentamicin]], [[kanamycin]], [[streptomycin]], etc.) used for the treatment of [[multi-drug-resistant tuberculosis|drug-resistant tuberculosis]] and cystic fibrosis can cause respiratory disorders, deafness and kidney failure.<ref>{{cite journal | vauthors = Prayle A, Watson A, Fortnum H, Smyth A | title = Side effects of aminoglycosides on the kidney, ear and balance in cystic fibrosis | journal = Thorax | volume = 65 | issue = 7 | pages = 654–658 | date = July 2010 | pmid = 20627927 | pmc = 2921289 | doi = 10.1136/thx.2009.131532 }}</ref><ref>{{cite journal | vauthors = Alene KA, Wangdi K, Colquhoun S, Chani K, Islam T, Rahevar K, Morishita F, Byrne A, Clark J, Viney K | title = Tuberculosis related disability: a systematic review and meta-analysis | journal = BMC Medicine | volume = 19 | issue = 1 | pages = 203 | date = September 2021 | pmid = 34496845 | pmc = 8426113 | doi = 10.1186/s12916-021-02063-9 | doi-access = free}}</ref>

The potential crisis at hand is the result of a marked decrease in industry research and development.<ref name="bbc">{{cite news|url=https://www.bbc.co.uk/news/health-21737844|title=BBC News&nbsp;– Antibiotics resistance 'as big a risk as terrorism' – medical chief| vauthors = Walsh F |publisher=Bbc.co.uk|access-date=12 March 2013|archive-url=https://web.archive.org/web/20180808002730/https://www.bbc.co.uk/news/health-21737844|archive-date=8 August 2018|url-status=live|work=BBC News|date=11 March 2013}}</ref><ref name="TB">{{cite journal | vauthors = Berida T, Adekunle Y, Dada-Adegbola H, Kdimy A, Roy S, Sarker S | title = Plant antibacterials: The challenges and opportunities | journal = Heliyon | volume = 10 | issue = 10 | pages = e31145 | date = May 2024 | pmid = 38803958 | pmc = 11128932 | doi = 10.1016/j.heliyon.2024.e31145 | doi-access = free | bibcode = 2024Heliy..1031145B}}</ref> Poor financial investment in antibiotic research has exacerbated the situation.<ref name="TheRealNews-2014-05-18">{{cite web | url=http://therealnews.com/t2/index.php?option=com_content&task=view&id=31&Itemid=74&jumival=11872 | title=Why Are Antibiotics Becoming Useless All Over the World? | vauthors = Khor M | author-link=Martin Khor |date=18 May 2014 | publisher=[[The Real News]] | access-date=18 May 2014 | archive-url=https://web.archive.org/web/20140518173348/http://therealnews.com/t2/index.php?option=com_content&task=view&id=31&Itemid=74&jumival=11872 | archive-date=18 May 2014 | url-status=live}}</ref><ref name="bbc" /> The pharmaceutical industry has little incentive to invest in antibiotics because of the high risk and because the potential financial returns are less likely to cover the cost of [[drug development|development]] than for other pharmaceuticals.<ref>{{cite news |title=Antibiotic Resistance: Why Aren't Drug Companies Developing New Medicines to Stop Superbugs?| vauthors = Nordrum A | website=International Business Times|year=2015}}</ref> In 2011, [[Pfizer]], one of the last major pharmaceutical companies developing new antibiotics, shut down its primary research effort, citing poor shareholder returns relative to drugs for chronic illnesses.<ref name="medpage">{{cite web|url=http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/24708|title=Pfizer Moves May Dim Prospect for New Antibiotics| vauthors = Gever J |date=4 February 2011|publisher=MedPage Today|access-date=12 March 2013 |archive-url=https://web.archive.org/web/20131214004508/http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/24708 |archive-date=14 December 2013|url-status=live}}</ref> However, small and medium-sized pharmaceutical companies are still active in antibiotic drug research. In particular, apart from classical synthetic chemistry methodologies, researchers have developed a combinatorial synthetic biology platform on single cell level in a [[high-throughput screening]] manner to diversify novel [[Lantibiotics|lanthipeptides]].<ref>{{cite journal | vauthors = Schmitt S, Montalbán-López M, Peterhoff D, Deng J, Wagner R, Held M, Kuipers OP, Panke S | title = Analysis of modular bioengineered antimicrobial lanthipeptides at nanoliter scale | journal = Nature Chemical Biology | volume = 15 | issue = 5 | pages = 437–443 | date = May 2019 | pmid = 30936500 | doi = 10.1038/s41589-019-0250-5 | s2cid = 91188986 | url = https://pure.rug.nl/ws/files/82569070/Brl_k_et_al_2019_Journal_of_Animal_Ecology.pdf | access-date = 12 April 2023 | archive-date = 18 April 2023 | archive-url = https://web.archive.org/web/20230418031100/https://pure.rug.nl/ws/files/82569070/Brl_k_et_al_2019_Journal_of_Animal_Ecology.pdf | url-status = live }}</ref>

In the 5–10 years since 2010, there has been a significant change in the ways new antimicrobial agents are discovered and developed – principally via the formation of public-private funding initiatives. These include [[CARB-X]],<ref>{{cite web |title=Overview |url=https://carb-x.org/about/overview/ |access-date=2023-03-28 |website=Carb-X|archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328115249/https://carb-x.org/about/overview/ |url-status=live }}</ref> which focuses on nonclinical and early phase development of novel antibiotics, vaccines, rapid diagnostics; Novel Gram Negative Antibiotic (GNA-NOW),<ref>{{cite journal |title=Novel Gram Negative Antibiotic Now |url=https://cordis.europa.eu/project/id/853979 |access-date=28 March 2023 |website=CORDIS |doi=10.3030/853979 |archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328115251/https://cordis.europa.eu/project/id/853979 |url-status=live }}</ref> which is part of the EU's [[Innovative Medicines Initiative]]; and Replenishing and Enabling the Pipeline for Anti-infective Resistance Impact Fund (REPAIR).<ref>{{cite web |title=About |url=https://www.repair-impact-fund.com/about/ |access-date=2023-03-28 |website=REPAIR Impact Fund|archive-date=23 January 2019 |archive-url=https://web.archive.org/web/20190123223739/https://www.repair-impact-fund.com/about/ |url-status=live }}</ref> Later stage clinical development is supported by the AMR Action Fund, which in turn is supported by multiple investors with the aim of developing 2–4 new antimicrobial agents by 2030. The delivery of these trials is facilitated by national and international networks supported by the Clinical Research Network of the [[National Institute for Health and Care Research]] (NIHR), European Clinical Research Alliance in Infectious Diseases (ECRAID) and the recently formed ADVANCE-ID, which is a clinical research network based in Asia.<ref>{{cite web |title=ADVANcing Clinical Evidence in Infectious Diseases (ADVANCE-ID) |url=https://sph.nus.edu.sg/2022/11/advancing-clinical-evidence-in-infectious-diseases-advance-id/ |access-date=2023-03-28 |website=sph.nus.edu.sg |archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328115252/https://sph.nus.edu.sg/2022/11/advancing-clinical-evidence-in-infectious-diseases-advance-id/ |url-status=live }}</ref> The [[Global Antibiotic Research and Development Partnership]] (GARDP) is generating new evidence for global AMR threats such as neonatal sepsis, treatment of serious bacterial infections and sexually transmitted infections as well as addressing global access to new and strategically important antibacterial drugs.<ref>{{cite web |date=2022-09-27 |title=About GARDP |url=https://gardp.org/about-gardp/ |access-date=2023-03-28 |website=GARDP|archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328115300/https://gardp.org/about-gardp/ |url-status=live }}</ref>

The discovery and development of new antimicrobial agents has been facilitated by regulatory advances, which have been principally led by the [[European Medicines Agency]] (EMA) and the [[Food and Drug Administration]] (FDA). These processes are increasingly aligned although important differences remain and drug developers must prepare separate documents. New development pathways have been developed to help with the approval of new antimicrobial agents that address unmet needs such as the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD). These new pathways are required because of difficulties in conducting large definitive [[Phases of clinical research|phase III clinical trials]] in a timely way.

Some of the economic impediments to the development of new antimicrobial agents have been addressed by innovative reimbursement schemes that delink payment of antimicrobials from volume-based sales. In the UK, a market entry reward scheme has been pioneered by the [[National Institute for Health and Care Excellence|National Institute for Clinical Excellence]] (NICE) whereby an annual subscription fee is paid for use of strategically valuable antimicrobial agents – [[cefiderocol]] and [[Ceftazidime/avibactam|ceftazidime-aviabactam]] are the first agents to be used in this manner and the scheme is potential blueprint for comparable programs in other countries.

The available classes of antifungal drugs are still limited but as of 2021 novel classes of antifungals are being developed and are undergoing various stages of clinical trials to assess performance.<ref>{{cite journal | vauthors = Hoenigl M, Sprute R, Egger M, Arastehfar A, Cornely OA, Krause R, Lass-Flörl C, Prattes J, Spec A, Thompson GR, Wiederhold N, Jenks JD | title = The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin | journal = Drugs | volume = 81 | issue = 15 | pages = 1703–1729 | date = October 2021 | pmid = 34626339 | pmc = 8501344 | doi = 10.1007/s40265-021-01611-0}}</ref>

Scientists have started using advanced computational approaches with supercomputers for the development of new antibiotic derivatives to deal with antimicrobial resistance.<ref name="TB" /><ref>{{cite news |title=Antibiotic resistance outwitted by supercomputers |url=https://medicalxpress.com/news/2021-11-antibiotic-resistance-outwitted-supercomputers.html |access-date=13 December 2021 |work=[[University of Portsmouth]]|archive-date=13 December 2021 |archive-url=https://web.archive.org/web/20211213175124/https://medicalxpress.com/news/2021-11-antibiotic-resistance-outwitted-supercomputers.html |url-status=live}}</ref><ref>{{cite journal | vauthors = König G, Sokkar P, Pryk N, Heinrich S, Möller D, Cimicata G, Matzov D, Dietze P, Thiel W, Bashan A, Bandow JE, Zuegg J, Yonath A, Schulz F, Sanchez-Garcia E | title = Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 46 | pages = e2113632118 | date = November 2021 | pmid = 34750269 | pmc = 8609559 | doi = 10.1073/pnas.2113632118 | bibcode = 2021PNAS..11813632K | doi-access = free}}</ref>