New drug target identified for antibiotic-resistant bacteria

Scientists have discovered a key mechanism that enables dangerous bacteria to develop resistance to antibiotics. These results provide a promising new drug target in the quest for new, effective antibiotics as the world faces the rising threat of antimicrobial resistance (AMR) and infections induced by bacterial microbes.

New drug target identified for antibiotic-resistant bacteria
Image Credit: John Innes Centre.

The research work explored the use of quinolone antibiotics for treating a number of bacterial infections, such as tuberculosis (TB). Quinolone antibiotics act by suppressing the bacterial enzymes—topoisomerase IV and gyrase—thus blocking the replication of DNA and the synthesis of RNA that are crucial for growth.

Quinolones are highly effective antimicrobial agents commonly used in the present medicine, but bacterial resistance to these drugs and other therapies is a major issue. Earlier studies had detected one certain resistance mechanism caused by the synthesis of pentapeptide repeat proteins (PRPs)—a group of molecules that also work as DNA gyrase inhibitors.

One of these molecules, known as MfpA, imparts quinolone resistance to Mycobacterium tuberculosis, the agent responsible for causing TB.

In this analysis, the researchers from John Innes Center and part of the team of Professor Tony Maxwell set out to explore how PRPs, like MfpA, function at the molecular level.

The team purified MfpA from Mycobacterium smegmatis—a close relative of M. tuberculosis—and demonstrated that it can suppress the supercoiling reaction of DNA gyrase, the focus of quinolone antibiotics in TB-causing mycobacteria.

Additional studies have shown that MfpA can prevent the poisoning of gyrase caused by quinolone antibiotics, thereby shielding the bacterial host cells from antibiotics.

With the help of X-ray crystallography, the team has demonstrated that MfpA attaches to the ATPase domain of gyrase and this fact shows its potential to suppress the supercoiling reactions and avoid quinolone poisoning.

We did not expect the exact mechanism of MfpA to be the prevention of DNA binding to the gyrase ATPase domain; this is a unique mode of action. We believe this understanding will help drive new ideas for antibiotic development among academics and researchers in the pharma industry.”

Tony Maxwell, Study Corresponding Author and Professor, John Innes Center

Additional analyses will include molecular modeling based on the MfpA-gyrase structure to develop small molecules that could imitate this interaction and provide more information on how it functions.

Quinolones and fluoroquinolones are broad-spectrum antibiotics that are active against a variety of Gram-positive and Gram-negative bacteria.

A new review by Professor Maxwell’s team underscores the mechanisms of action of fluoroquinolone antibiotics and discusses the promising mechanisms that lead to cell death. The study also considered the resistance to quinolone antibiotics and how quinolone therapy can promote resistance to non-quinolone antibiotics.

Source:
Journal reference:

Feng, L., et al. (2021) The pentapeptide-repeat protein, MfpA, interacts with mycobacterial DNA gyrase as a DNA T-segment mimic. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2016705118.

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