Microbiology

Biography

Biography: Pavel Dibrov

Abstract

Statement of the Problem: The present crisis in antibiotic development and administering was precipitated not only by decades of global misuse of broad-spectrum antibiotics and resulting proliferation of multi-drug resistant strains, but also by a general strategy in antibiotic design, when a very limited set of prokaryotic enzymes and metabolic pathways was ever targeted. The situation calls for urgent intensification of the search for non-traditional antimicrobial targets. Methodology & Theoretical Orientation:  The Na⁺-translocating NADH:ubiquinone oxidoreductase (Na⁺-NQR) is a key respiratory enzyme in many aerobic pathogens, including a widespread and notoriously difficult to treat Chlamydia trachomatis. Inhibition of Na⁺-NQR was predicted to arrest bacterial energization and proliferation, and ultimately disrupt the infectious process.  To examine this prediction, a new furanone inhibitor of Na⁺-NQR, PEG-2S, was designed and assayed for its anti-chlamydial activity in cell culture models of infection.  Findings: The presented work confirmes that Na⁺-NQR is critical for the Chlamydia trachomatis infectious process.  A newly designed PEG-2S inhibited intracellular proliferation of Chl. trachomatis with a half-minimal concentration in the submicromolar range without affecting the viability of mammalian cells or selected species representing benign intestinal microflora.  Infection by Chl. trachomatis increased H⁺ and Na⁺ concentration in the infected mammalian cell.  Addition of PEG-2S blocked these changes in ion balance induced by Chl. trachomatis infection. PEG-2S also inhibited the Na⁺-NQR activity in sub-bacterial membrane vesicles isolated from Vibrio cholerae when added at very low (nanomolar) concentrations.  Conclusion & Significance: The obtained results demonstrate that Na⁺-NQR is critical for the bacterial infectious process and is susceptible to a precisely targeted bactericidal compound in situ. PEG-2S opens a new line of narrowly targeted inhibitors of NQR and is serving as a molecular platform for the development of “individually tailored” anti-NQR remedies narrowly targeting specific pathogens.