New study reveals a whole new class of antibiotics that “can shut down one of the ways bacteria fight back against antibiotics” and help reverse antibiotic resistance in bacteria that cause conditions such as pneumonia, sepsis, and UTIs.

Carbapenems, such as meropenem, are a class of antibiotics that are often used as a “last resort” when other antibiotics, such as penicillin, have failed to treat serious, multi-drug resistant infections.

However, certain bacteria have discovered a way to resist carbapenem treatment by creating enzymes known as metallo-beta-lactamases (MBLs), which break down carbapenem antibiotics and prevent them from working.

Researchers from the Ineos Oxford Institute (IOI) for Antimicrobial Research at the University of Oxford and several other institutions across Europe discovered that a new class of enzyme blockers known as indole carboxylates can stop MBL resistance enzymes from working, allowing the antibiotic to attack and kill bacteria like E. coli in the lab and in mice infections.

The team first evaluated hundreds of thousands of molecules to determine which would bind strongly to MBLs and prevent them from working, as well as which would not react with any human proteins, leading to the finding of indole carboxylates as intriguing new options.

With the help of crystallography to zoom in and take a closer look at how they work, They discovered that these prospective medications bind to MBLs in a completely different way than any other drug – they mimic the interaction of the antibiotic with the MBLs. Due to this new cunning Trojan Horse approach, these potential medications are highly powerful against a broad range of MBL-producing superbugs.

After discovering the drugs, the researchers chemically altered them to make them more effective and then tested them in combination with carbapenems against multidrug-resistant bacteria in both lab dishes and animals. The possible new drugs were found to be 5 times more effective at treating severe bacterial infections when used in combination with carbapenems than carbapenems alone, and at a lower dose. Importantly, in mice, these potential medications have only minor adverse effects.

Carbapenems work similarly to penicillin and other beta-lactam antibiotics in that they prevent bacteria from creating new cell walls as they try to expand and reproduce, killing the bacteria in the process. Carbapenems are more stable than similar antibiotics, and many of the strategies bacteria use to resist antibiotics do not work with carbapenems.

Resistance to carbapenems, on the other hand, evolved from genes that code for MBLs, which can quickly spread from bacteria to bacteria. There is currently no licensed drug that targets MBLs, and only one is in clinical studies, therefore new therapies to overcome resistance, protect carbapenems, and keep these valuable medicines working for longer are urgently needed.

Antimicrobial resistance, according to the World Health Organization (WHO), will cause 10 million deaths per year by 2050, surpassing cancer-related mortality and becoming one of humanity’s most significant health issues.

Professor Christopher Schofield, Academic Lead (Chemistry) of the University of Oxford’s Ineos Oxford Institute, said:

“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) at the University of Oxford’s Ineos Oxford Institute, added:

“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.”

Source: Nature Chemistry

Image Credit: Getty

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