Researchers have identified essential mechanisms that allow lethal bacteria to resist antibiotics.
The findings offer a potential new drug target for the discovery of effective new antibiotics as we face the growing risk of antimicrobial resistance (AMR) and infections. caused by bacterial pathogens.
The study examined quinolone antibiotics used to treat a range of bacterial infections, including TB (tuberculosis). Quinolones work by inhibiting bacterial enzymes, gyrase and topoisomerase IV, thus inhibiting DNA reproduction and RNA synthesis necessary for growth.
They are highly successful antimicrobial agents widely used in conventional medicine, but bacterial side effects and other treatments are a major problem.
Previous studies had identified one immune mechanism induced by the production of pentapeptide repeating proteins (PRPs), a family of molecules that are also DNA protectors of gyrase.
One of these, called MfpA, counteracts quinolone against Mycobacterium tuberculosis, the causative agent of TB.
In this study John Innes Center researchers in the group of Professor Tony Maxwell began to discover how PRPs like MfpA, function at the molecular level.
They cleared MfpA from Mycobacterium smegmatis, close relatives of M. tuberculosis, and showed that it can inhibit the supercoiling reaction of DNA gyrase, the target of quinolones in TB causing mycobacteria.
Further studies have shown that MfpA can inhibit gyrase poisoning with quinolones, thus protecting bacterial host cells from the antibiotic.
Using X-ray crystals, the researchers showed that MfpA binds to the ATPase domain of gyrase, which explains its ability to inhibit the supercoiling reaction and prevents quinolone poisoning.
We did not expect MfpA to be the true mechanism of inhibition of DNA binding to ATPase gyrase domain; this is a specific mode of action. W.He believes this understanding will help guide new ideas for antibiotic development among academics and researchers in the pharma industry. “
Tony Maxwell, Associate Research Author and Professor, John Innes Center
Further study work will involve molecular modeling based on the structure of MfpA-gyrase to design small molecules that could simulate this interaction and provide more insight into how it works.
Source:
Magazine Reference:
Feng, L., et al. (2021) The pentapeptide-repeating protein, MfpA, interacts with mycobacterial DNA cyc as a T-segment DNA mimic. PNAS. doi.org/10.1073/pnas.2016705118.