Enzyme Blocker Shown to be Effective at Reversing Resistance to Carbapenem Antibiotics

Enzyme Blocker Shown to be Effective at Reversing Resistance to Carbapenem Antibiotics

While the world is dealing with the SARs-CoV-2 pandemic, another pandemic is raging that has the potential to be far more serious. There has been a major increase in infections caused by antibiotic-resistant microbes, with some bacteria now resistant to virtually all classes of antibiotics making treatment extremely difficult. According to the UK Health Security Agency, in 2020, one in five people had an infection that was caused by bacteria resistant to at least one commonly used antibiotic.

Antibiotic resistance is likely to develop over time. Bacteria evolve and become resistant by developing an ability to stop the drugs working, develop the ability to pump antibiotics out of their cells, or mutations arise that make the drugs less effective. The problem is now the rate at which resistance is developing and the lack of new antibiotics coming to market.

One notable example, although there are many, is the bacteria staphylococcus aureus, which is the leading cause of skin and soft tissue infections such as abscesses and cellulitis. Methicillin-resistant S. aureus (MRSA) is one strain of the bacteria that no longer responds to the antibiotic methicillin and closely related antibiotics that have previously been used to treat S. aureus infections. that makes MRSA infections extremely difficult to treat and MRSA infections can be fatal.

Unfortunately, developing new antibiotics is a very long and expensive process and many pharmaceutical companies have stopped research into new antibiotics altogether as it is not profitable. The last totally new class of antibiotic was developed in the late 1980s. Instead, pharma firms are concentrating on new anti-cancer drugs.

There may be solutions that are more cost-effective than developing new antibiotics, and one approach has been developed by a team of researchers headed by the Ineos Oxford Institute (IOI) for Antimicrobial Research at the University of Oxford. They have developed a method of reversing antibiotic resistance in gram-negative bacteria such as those that sepsis and pneumonia. Their approach uses enzyme blockers called indole carboxylates (InCs), and they have been shown to improve the effectiveness of carbapenem antibiotics.

Carbapenems, such as meropenem, are essential, highly effective antibiotics that serve as a last resort for treating severe or high-risk bacterial infections, including infections caused by suspected multidrug-resistant (MDR) bacteria. Carbapenems are beta-lactam antibacterials that have a broad spectrum of activity against many Gram-positive and Gram-negative bacteria and work by preventing bacteria from forming new cell walls when they multiply, which kills the bacteria.

Most of the mechanisms used by bacteria to resist antibiotics do not work on carbapenems, but the efficacy of these drugs against gram-negative bacteria is being increasingly compromised by metallo-β-lactamases (MBLs), which break down carbapenem antibiotics rendering them ineffective. To combat this, the researchers screened hundreds of thousands of compounds to see if any attached to MBLs to prevent them from working and would also not interact with human proteins. InCs were the best candidates.

The researchers found InCs inhibit the activity of metallo-β-lactamase (MBL) enzymes, which allows β-lactam antibiotics to attack and kill bacteria. The researchers demonstrated the effectiveness of InCs against resistant E. coli bacteria in the lab and in vivo in murine infections. The researchers determined they bind to MBLs in a way that is completely different from other drugs, essentially mimicking the interaction between MBL and antibiotics. The researchers then tweaked the molecules to make them more effective against carbapenem antibiotics. One of the InCs, InC58, made treatment with meropenem five times more effective than treatment with meropenem alone, and allowed meropenem to be used at a less concentrated dose.

“This research is the culmination of years of work, from screening huge libraries of chemicals, through to testing the best drug candidates in preclinical 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.” said study lead researcher, Christopher Schofield, PhD.

You can read more about the study in the paper – Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors – which was recently published in Nature Chemistry. DOI: 10.1038/s41557-021-00831-x