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

• Published in: Canadian journal of physiology and pharmacology 2017-05, Vol.95 (5), p.595-603
• Main Authors: Dibrov, Pavel, Dibrov, Elena, Maddaford, Thane G, Kenneth, Melissa, Nelson, Jordan, Resch, Craig, Pierce, Grant N
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibiotic design; Antibiotics; Bacteria; bactérie; Care and treatment; Cells; Chlamydia; Chlamydia infections; Chlamydia trachomatis; Chlamydia trachomatis - drug effects; Cholera toxin; conception d’antibiotiques; Disease transmission; Drug Design; Enzymes; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Health aspects; HEK293 Cells; HeLa Cells; Homeostasis - drug effects; Humans; infection; Microbiota (Symbiotic organisms); NADH : ubiquinone oxydoréductase induisant la translocation des ions Na; NADH, NADPH Oxidoreductases - antagonists & inhibitors; NQR; Pharmacology; Physiology; translocating NADH:ubiquinone oxidoreductase; Vibrio cholerae
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2016-0505

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 (IC 50 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.