{"id":514428,"date":"2024-07-10T16:31:03","date_gmt":"2024-07-10T19:31:03","guid":{"rendered":"https:\/\/revistapesquisa.fapesp.br\/?p=514428"},"modified":"2024-07-10T16:31:03","modified_gmt":"2024-07-10T19:31:03","slug":"testing-of-candidate-antibiotics-has-increased-in-the-last-decade","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/testing-of-candidate-antibiotics-has-increased-in-the-last-decade\/","title":{"rendered":"Testing of candidate antibiotics has increased in the last decade"},"content":{"rendered":"

In May 2023, there was promising news in the fight against drug-resistant bacteria. With the help of AI, researchers from Canada and the USA identified a compound that acted potently and specifically against Acinetobacter baumannii<\/em>, which often causes serious lung and urinary tract infections in hospital inpatients. The pathogen is on a list drawn up by the World Health Organization (WHO) in 2017 of bacteria against which new treatments are urgently needed because current antibiotics can no longer eliminate them (see report on page 12<\/em>).<\/p>\n

The team, led by James Collins of the Massachusetts Institute of Technology (MIT), USA, and Jonathan Stokes of McMaster University, Canada, trained a computational model to recognize the properties of 480 compounds that have some effect on A. baumannii<\/em> from among the 7,684 tested to combat the microorganism. They then presented the model with another 6,680 molecules whose antibiotic action is unknown, so that the program could identify those most likely to kill the pathogen. Within hours, the list of 6,680 compounds was whittled down to 240, something that would have taken days or months using traditional testing methods. Forty of those 240 molecules proved capable of inhibiting the growth of A. baumannii<\/em> in the laboratory. One\u2014called abaucine\u2014did particularly well and progressed to animal testing. There is still a long way to go, however, before it might become an antibiotic for human use.<\/p>\n

Despite reducing the time spent screening compounds, computational modeling and AI alone are unlikely to solve the problem of antibiotic resistance. The issue is as old as the use of these compounds in modern medicine, and according to experts, a range of measures are needed, from the strictly controlled use of these medicines in human and animal healthcare to the prevention of infections through good hygiene and vaccination whenever possible, in addition to the development of new drugs.<\/p>\n\n \n \n \n <\/picture>Alexandre Affonso\/Pesquisa FAPESP<\/span>\n

The first known synthetic antibiotic was arsphenamine, a compound containing arsenic that was identified by German doctor Paul Ehrlich (1854\u20131915) in 1907, although there is evidence that treatments based on natural products had been used since ancient times.<\/p>\n

In tests conducted on rabbits in 1909, Ehrlich and Japanese bacteriologist Sahachiro Hata (1873\u20131938) demonstrated that arsphenamine was capable of eliminating the bacteria that causes syphilis (Treponema pallidum<\/em>) without killing the animals. Their work paved the way for the compound to be used from the following year onward\u2014sold under the name Salvarsan\u2014to treat the sexually transmitted disease, which humankind had been living with for centuries. In 1928, however, first reports started to emerge of cases where Salvarsan had no effect against some varieties of T. pallidum<\/em>.<\/p>\n

The same thing happened with penicillin. The compound was identified in 1928 by Scottish physician Alexander Fleming (1881\u20131955), discovered in a culture of the bacteria Staphylococcus aureus<\/em> that had been accidentally contaminated with a fungus of the genus Penicillium <\/em>in his laboratory at Saint Mary’s Hospital, London. <\/em>It was soon being used to treat infections. It would take more than a decade for other scientists to purify the active ingredient and implement large-scale production. However, even before the widespread use of penicillin saved the lives of thousands of soldiers in World War II, there were signs that bacteria could become resistant to the drug.<\/p>\n

Fleming knew this and began calling attention to the problem, including in a speech he gave after winning the Nobel Prize for Medicine in 1945. \u201cIt is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them. There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to nonlethal quantities of the drug, make them resistant,\u201d said the Scottish doctor.<\/p>\n

And that is exactly what has happened. The widespread use of these compounds in human and animal healthcare and agriculture has led to the emergence of bacteria resistant to various antimicrobials. \u201cFleming\u2019s predictions turned out to be accurate: the incorrect use, sometimes real abuse, of antibiotics, speeds up the development and spread of bacteria resistant to them,\u201d wrote Marco Terreni, a chemist from the University of Pavia, Italy, and colleagues in a review article on new antibiotics, published in the journal Molecules<\/a> <\/em>in 2021.<\/p>\n

\"\"

USDA-ARS<\/span><\/a> Andrew Moyer (1899\u20131959), who discovered how to mass-produce penicillinUSDA-ARS<\/span><\/p><\/div>\n

\u201cIt\u2019s like a game of chess,\u201d says biochemical pharmacist Ilana Camargo, head of the Molecular Epidemiology and Microbiology Laboratory (LEMiMo) at the University of S\u00e3o Paulo (USP), S\u00e3o Carlos campus. Her group is characterizing bacteria resistant to multiple antibiotics and identifying new compounds with the potential to combat them. Their most recent discovery is a synthetic derivative of plantaricin 149, a peptide produced by the bacteria Lactobacillus plantarum<\/em>. During in vitro<\/em> tests, the molecule eliminated 60 bacteria of different species and strains, each with varying degrees of resistance to existing drugs on the market, according to an article published in Antibiotics <\/em><\/a>in February 2023. \u201cWhenever we think we have a type of bacteria in check with a new antibiotic, it soon finds a way to escape,\u201d Camargo says.<\/p>\n

Dozens of new antibiotics have been identified since the turn of the twentieth century, from a wide range of classes and with many different mechanisms of action. A significant proportion of them\u2014more than 75%, according to some experts\u2014are of natural origin, produced by other microorganisms. For a long time, one of the champions at providing new antibiotics were bacteria of the genus Streptomyces<\/em>. A review article published by British researchers in the journal Current Opinion in Microbiology<\/em><\/a> in 2019 estimates that these bacteria, found in soil and decaying vegetation, were the source of 55% of antibiotics discovered between 1945 and 1978, including neomycin, streptomycin, grisemycin, and chloramphenicol. The problem is that bacteria almost always become resistant to new antibiotics soon after they are introduced to the market. In some cases, they become resistant to more than one antibiotic (see timeline on pages 19 and 21<\/em>).<\/p>\n

Until the late 1970s, major pharmaceutical companies worked around the issue by continuously launching new antibiotics, produced using molecules extracted from other bacteria or fungi and with different chemical structures. But as time went on, these compounds became ever harder to find in the most commonly studied microorganisms. \u201cThe lowest-hanging fruit had already been picked,\u201d says Camargo, who works at the Center for Innovation in Biodiversity and Drug Discovery (CIBFAR), one of the Research, Innovation, and Diffusion Centers (RIDCs) funded by FAPESP. \u201cIt became necessary to invest in research into modifying the chemical structure of known molecules,\u201d he explains.<\/p>\n

The previous ease with which new antibiotics were obtained and their high performance created a false sense of security, alongside a major change that occurred in the pharmaceutical industry in the early 1980s. A new generation of managers were taking the helm at many large companies, redirecting investments toward the development of more expensive and profitable drugs to treat cancer and diseases associated with lifestyle, such as diabetes, explained Matthew Todd of University College London, UK, and colleagues in the journal Wellcome Open Research<\/em><\/a> in 2021. \u201cThe central problem of the empty antibiotic pipeline is not scientific but economic,\u201d they emphasized.<\/p>\n

The amount of money companies made selling new antibiotics, which were more expensive and difficult to obtain, rarely covered the cost of development. And according to some experts, profits fell even further when generic versions of these medicines hit the market. \u201cAt the time, many major pharmaceutical companies shuttered entire departments and ended antibiotic screening and development programs,\u201d says Brazilian biochemist Andr\u00e9a Dessen, head of the Bacterial Pathogenesis Group at the Institute of Structural Biology (IBS) in Grenoble, France.<\/p>\n<\/div>

\n \n \n \n <\/picture>Alexandre Affonso\/Pesquisa FAPESP<\/span><\/div>
\n

Work that was previously done by the pharmaceutical industry was left to universities and startups, which were unable to complete the development cycle of a new medication even when they did find promising molecules. \u201cAcademic laboratories are not equipped to carry out the entire process and many small companies attempting to do so go out of business because they are unable to maintain the necessary level of investment,\u201d explains Dessen.<\/p>\n

The result was a drop in the number of new antibiotics based on innovative molecules, with the following decades dubbed a \u201cvacuum of discovery.\u201d In the USA alone, the number declined by 56% between the periods 1983\u20131987 and 1998\u20132002, according to a survey<\/a> by Dr. Jack Edwards Jr. of the University of California, Los Angeles.<\/p>\n

The world began to pay greater attention to the issue in 2014, when the WHO published its first global report on antimicrobial resistance, showing that the problem was already widespread across the planet. Over the last two decades, more than 50 initiatives have been created\u2014public and private, Brazilian and international\u2014to stimulate the development of new antibiotics for resistant bacteria.<\/p>\n

But a review of the main programs in the USA, EU, and UK, led by Elias Mossialos, a health policy expert from Imperial College London, UK, identified a lack of coordination between the different initiatives and found that most incentives still focus on the early phases of research, making it difficult for new drugs to reach the market. \u201cThese initiatives represent progress, but they are insufficient given the scale of the problem,\u201d says Dessen.<\/p>\n

Nineteen new antibiotics and four combinations of existing ones were approved for sale between 2013 and 2022. None of them belong to a new class capable of combating drug-resistant strains of bacteria, according to a review article published in the Journal of Antibiotics<\/em><\/a> in 2023 by a team led by Mark Blaskovich of the University of Queensland, Australia. In the past decade, however, there has been an increase in the number of candidate antibiotics in one of the three phases of human testing needed before authorization for clinical use. There were 40 in 2011 and 62 in 2022. Most (82%) were in clinical trial phases 1 and 2, at which stage some compounds are ruled out due to toxicity or failure to produce the desired effect.<\/p>\n

Of the 62 currently being tested, 34 were innovative molecules\u2014to offer a comparison, 159 new drugs have been launched for different forms of cancer worldwide since 2012. \u201cThe impetus has been rising, but many of the compounds in phase 2 or 3 trials are adaptations of known structures, which increases the risk of microorganisms becoming resistant to them,\u201d says Dessen.<\/p>\n

Project<\/strong>
\nCIBFar \u2013 Center for Innovation in Biodiversity and Pharmaceuticals (n\u00ba 13\/07600-3<\/a>); Grant Mechanism<\/strong> Research, Innovation, and Dissemination Centers (RIDC); Principal Investigator<\/strong> Glaucius Oliva (IFSC-USP); Investment<\/strong> R$53,765,242.70.<\/p>\n

Scientific articles<\/strong>
\nLIU, G. et al<\/em>. Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii<\/em><\/a>. Nature Chemical Biology<\/strong>. May 25, 2023.
\nTERRENI, M. et al<\/em>. New antibiotics for multidrug-resistant bacterial strains: Latest research developments and future perspectives<\/a>. Molecules<\/strong>. May 2, 2021.
\nRIGHETTO, G. M. et al<\/em>. Antimicrobial activity of an Fmoc-Plantaricin 149 derivative peptide against multidrug-resistant bacteria<\/a>. Antibiotics<\/strong>. Feb. 15, 2023.
\nHUTCHINGS, M. I. et al<\/em>. Antibiotics: Past, present and future<\/a>. Current Opinion in Microbiology<\/strong>. Nov. 13, 2019.
\nKLUG, D. M. et al<\/em>. There is no market for new antibiotics: This allows an open approach to research and development.<\/a> Wellcome Open Research<\/strong>. June 21, 2021.
\nSPELLBERG, B. et al<\/em>. Trends in antimicrobial drug development: Implications for the future<\/a>. Clinical Infectious Diseases<\/strong>. May 1, 2004.
\nWHO<\/strong>. Antimicrobial resistance global report on surveillance<\/a>. 2014.
\nSIMPKIN, V. L. et al<\/em>. Incentivising innovation in antibiotic drug discovery and development: Progress, challenges and next steps<\/a>. The Journal of Antibiotics<\/strong>. Nov. 1, 2017.
\nBUTLER, M. S. et al<\/em>. Antibiotics in the clinical pipeline as of December 2022<\/a>. The Journal of Antibiotics<\/strong>. June 8, 2023.<\/p>\n","protected":false},"excerpt":{"rendered":"The number of compounds entering clinical use is still too low to combat multidrug-resistant bacteria","protected":false},"author":16,"featured_media":514400,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[156,159],"tags":[247],"coauthors":[105],"class_list":["post-514428","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-cover","category-science","tag-medicine"],"acf":[],"_links":{"self":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/514428","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/users\/16"}],"replies":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/comments?post=514428"}],"version-history":[{"count":3,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/514428\/revisions"}],"predecessor-version":[{"id":520764,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/514428\/revisions\/520764"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media\/514400"}],"wp:attachment":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media?parent=514428"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/categories?post=514428"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/tags?post=514428"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/coauthors?post=514428"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}