via Imperial College London
Scientists have discovered a new potential treatment that has the ability to reverse antibiotic resistance in bacteria that cause conditions such as sepsis, pneumonia, and urinary tract infections.
Carbapenems, such as meropenem, are a group of vital often ‘last-resort’ antibiotics used to treat serious, multi-drug resistant infections when other antibiotics, such as penicillin, have failed. But some bacteria have found a way to survive treatment with carbapenems, by producing enzymes called metallo-beta-lactamases (MBLs) that break down the carbapenem antibiotics, stopping them from working.
Highly collaborative research, conducted by scientists from the Ineos Oxford Institute (IOI) for Antimicrobial Research at the University of Oxford and several institutions across Europe, found that the new class of enzyme blockers, called indole carboxylates, can stop MBL resistance enzymes working leaving the antibiotic free to attack and kill bacteria such as E. coli in the lab and in infections in mice.
The new research, published in Nature Chemistry, was funded by the Innovative Medicines Initiative (IMI) through the European Lead Factory (ELF) and the European Gram-Negative Antibacterial Engine (ENABLE) programmes.
The researchers first screened hundreds of thousands of chemicals to see which would attach tightly to MBLs to stop them working, and which didn’t react with any human proteins, leading to the discovery of the indole carboxylates as promising new candidates. Using a process called crystallography to zoom in to take a closer look at how they work, the researchers found these potential drugs attach to MBLs in a completely different way to any other drugs – they imitate the interaction of the antibiotic with the MBLs. This clever Trojan Horse trick allows these potential drugs to be highly effective against a very wide range of MBL-producing superbugs.
After their initial discovery, the researchers chemically changed aspects of the drugs to make them as effective as possible, and tested them in combination with carbapenems against multi-drug resistant bacteria in both dishes in the lab and in mice. The potential new drugs in combination with carbapenems were found to be 5 times more potent at treating severe bacterial infections than carbapenems alone, and at a less concentrated dose. Importantly, these potential drugs show only mild side effects in mice.
Carbapenems work in a similar way to penicillin and other related antibiotics called beta-lactams – they stop bacteria from forming new cell walls when they try to grow and multiply, which kills the bacteria. Carbapenems are more stable than other similar antibiotics, and many of the methods bacteria employ to resist antibiotics don’t work on carbapenems.
However, resistance arose to carbapenems through, for example, genes that code for MBLs, which can quickly pass from bacteria to bacteria. There is no licensed drug that targets MBLs, and only one in clinical trials – so there is an urgent need to find new drugs that overcome resistance, protect carbapenems and keep these precious medicines working for longer.
The World Health Organisation (WHO) estimates that by 2050, 10 million deaths will be due annually to antimicrobial resistance, overtaking the number of cancer related deaths – making it one of the most pressing health problems faced by humanity today.
Professor Christopher Schofield, Academic Lead (Chemistry), Ineos Oxford Institute at the University of Oxford, said, ‘An increase in antimicrobial resistance is absolutely inevitable. It a massive problem because collectively we haven’t been making enough new clinically useful antibiotics. As a society we must find ways both to make new antibiotics and protect the ones we have. The alternative is that routine modern medicine will be disrupted in a manner simply too horrendous to conceive.
‘The collaborative efforts of academics and industry scientists have discovered a brand new class of drug that can shut down one of the ways bacteria fight back against antibiotics. This research is the culmination of years of work, from screening huge libraries of chemicals, through to testing the best drug candidates in pre-clinical studies in the lab. We are actively progressing this new drug type towards clinical trials in people, most importantly in lower and middle income countries where resistance to carbapenem antibiotics is widespread.’
Professor Tim Walsh, Academic Lead (Biology), Ineos Oxford Institute at the University of Oxford, said, ‘Academia, given the space to create, can produce something amazing – and that’s what we have seen here. With the fantastic support we have received from INEOS, we can replicate this type of drug discovery programme within the IOI for multiple different bacterial targets and applications.
‘As well as drugs that overcome resistance to current antibiotics, in the IOI we wish to discover entirely new types of antibiotics – not only to fight bacteria that cause infections in humans, but in bacteria that affect farm animals. These animals, such as chickens and pigs, are a source of human antimicrobial resistance, so we’re looking to develop drugs to use exclusively in agriculture and help protect against multidrug resistant infections.’
More from: University of Oxford
The Latest on: Reversing antibiotic resistance
- Recent Change of -13.82% in the Iterum Therapeutics plc (ITRM) market price might lead to pleasant surpriseson August 17, 2022 at 11:02 am
Iterum Therapeutics plc (ITRM) is priced at $0.24 after the most recent trading session. At the very opening of the session, the stock price was $0.28 and reached a high price of $0.2849, prior to ...
- White oral lesions in neonate with COVID-19on August 17, 2022 at 5:27 am
A 4-week-old boy presents with creamy white patches on his lips, right and left buccal mucosa, palate, and tongue.
- Iterum Therapeutics plc: Iterum Therapeutics Announces Date of 1-for-15 Reverse Share Spliton August 17, 2022 at 1:36 am
Iterum Therapeutics plc (Nasdaq: ITRM) (the "Company"), a clinical-stage pharmaceutical company focused on developing next generation ...
- Iterum Therapeutics Announces Date of 1-for-15 Reverse Share Spliton August 16, 2022 at 6:02 pm
Iterum Therapeutics plc (Nasdaq: ITRM) (the “Company”), a clinical-stage pharmaceutical company focused on developing next generation oral and IV antibiotics to treat infections caused by multi-drug ...
- T2 Biosystems, Inc. (TTOO) CEO John Sperzel on Q2 2022 Results - Earnings Call Transcripton August 15, 2022 at 8:00 pm
CEO Q2 2022 Results Earnings Conference Call August 15, 2022, 04:30 PM ET Company Participants Emma Poalillo - Investor Relations, Gilmartin ...
- New Drug Candidate Treats Over 300 Drug Resistant Bacteriaon August 15, 2022 at 6:28 pm
They are characterized by strong cell walls that make them increasingly resistant to available antibiotics, and thus notoriously difficult to treat. Effective treatment options often have negative ...
- New tRNA promotes synthesis of streptomyces antibioticson August 15, 2022 at 9:15 am
A research team led by Prof. Liu Guangxiu from the Northwest Institute of Eco-Environment and Resources of the Chinese Academy of Sciences (CAS) has isolated a fast-growing desert streptomycete from ...
- Different Takes: Ways To Outmaneuver Antibiotic-Resistant TB; ACAM2000 Monkeypox Shots Could Be Riskyon August 12, 2022 at 9:44 am
ACAM2000 Needs Full Review Before Being Used Against Monkeypox The Food and Drug Administration licensed ACAM2000 in 2007 to immunize people at high risk of smallpox infection. There is moderate ...
- TB is good at resisting antibiotics. Here are some new ideas to outsmart the bacteriaon August 11, 2022 at 8:41 am
Two new studies draw on data from more than 12,000 patients to help figure out ways to battle antibiotic-resistant tuberculosis.
- Antibiotic Resistance Genes of Mothers and Neonates in Low and Middle Income Countrieson August 7, 2022 at 8:00 am
A team of international researchers examined the presence of antibiotic resistance genes (ARGs) in the gut microbiota of 35,040 mothers and their 36,285 ba | Health And Medicine ...
via Bing News
The Latest on: Reversing antibiotic resistance
via Google News