Study shows impact of ‘reverse antibiotic’ on gram negative bacteria

Scientists from Skoltech and MSU have studied the antibiotic nybomycin which may be effective against bacteria resistant to other antibiotics. Their research was published in the journal Antimicrobial agents and chemotherapy.

All bacterial cells contain topoisomerases, an important group of enzymes that help manage spatial difficulties arising from bacterial cell division associated with circular DNA replication. Topoisomerases can be of two types, I and II, depending on the breaks they produce in DNA (single-stranded or double-stranded).

Type II often acts as a target for antibiotics, including fluoroquinolones (FQ), a common group of antibiotics that includes levofloxacin, ciprofloxacin, and others. Unfortunately, bacteria easily acquire resistance to FQs through mutations in the genes encoding topoisomerase. The emergence of resistant pathogenic strains is a global problem in healthcare, therefore, identifying alternative pathways to counteract their persistence is the current frontier in drug discovery.

The nybomycins reported as “reverse antibiotics” are able to block fluroquinolone resistant DNA gyrase (one of the type II topoisomerases). Previously, this effect was observed only in Gram-positive bacteria (bacteria can be either Gram-positive or Gram-negative, depending on the structure of their cell wall).

A team led by Olga Dontsova, professor at Skoltech and Moscow State University, demonstrated the impact of the “reverse antibiotic” on Gram-negative bacteria and showed for the first time that nybomycin can also be effective against unstable topoisomerases.

“It is interesting to note that the first type II topoisomerase inhibitors were found among quinolones, artificially synthesized molecules. There are now more and more natural molecules effective against the same target. Nybomycin, a natural topoisomerase II inhibitor, disrupts fluoroquinolone resistant gyrases, which means it can be used when fluoroquinolones, the classic gyrase inhibitors, are not working.

This is the first study to examine the details of topoisomerase II inhibition in gram-negative bacteria using nybomycin which blocks fluoroquinolone-sensitive and fluoroquinlone-resistant forms of gyrase in Escherichia coli.

Ilya Osterman, Principal Investigator, Skoltech Center for Life Sciences

According to Olga Dontsova: “Finding ways to overcome bacterial resistance to antibiotics is particularly important in pandemics, when secondary bacterial infections that are difficult to control often develop.”