Development of a novel rationally designed antibiotic to inhibit a nontraditional bacterial target

Abstract

The search for new nontraditional targets is a high priority in antibiotic design today. Bacterial membrane energetics based on sodium ion circulation offers potential alternative targets. The present work identifies the Na+-translocating NADH:ubiquinone oxidoreductase (Na+-NQR), a key respiratory enzyme in many microbial pathogens, as indispensible for the Chlamydia trachomatis infectious process. Infection by Chlamydia trachomatis significantly increased first H+ and then Na+ levels within the host mammalian cell. A newly designed furanone Na+-NQR inhibitor, PEG-2S, blocked the changes in both H+ and Na+ levels induced by Chlamydia trachomatis infection. It also inhibited intracellular proliferation of Chlamydia trachomatis with a half-minimal inhibitory concentration in the submicromolar range but did not affect the viability of mammalian cells or bacterial species representing benign intestinal microflora. At low nanomolar concentrations (IC50 value = 1.76 nmol/L), PEG-2S inhibited the Na+-NQR activity in sub-bacterial membrane vesicles isolated from Vibrio cholerae. Taken together, these results show, for the first time, that Na+-NQR is critical for the bacterial infectious process and is susceptible to a precisely targeted bactericidal compound in situ. The obtained data have immediate relevance for many different diseases caused by pathogenic bacteria that rely on Na+-NQR activity for growth, including sexually transmitted, pulmonary, oral, gum, and ocular infections.