title: Synergistic efficacy of Bisbenzimidazole and Carbonyl Cyanide 3-Chlorophenylhydrazone combination against MDR bacterial strains.
abstract: Activation of efflux systems and the formation of biofilm are majorly adapted by microbes to resist antimicrobial agents. PPEF (bisbenzimidazole) targeting topoisomerase IA is observed to be an effective bactericidal agent against both Gram-positive and Gram-negative bacterial strains and thus can be developed as potent broad-spectrum antibiotic against MDR strains. PPEF treatment did not cause target specific mutation instead it leads to up-regulation of efflux gene in E. coli K12 as a mechanism of resistance. Microscopy, fluorescence spectroscopy and flow cytometry result demonstrate higher accumulation of PPEF in efflux gene deleted E. coli K12 mutants, and also suggest that Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP), resist the efflux of PPEF, and thus increases efficacy of PPEF. Herein, we report, PPEF and CCCP synergistically killed the persistent bacterial cells, which are not killed by PPEF alone. The above two compounds together inhibited biofilm formation, eradicate preformed biofilms and kills the biofilm cells of P. aeruginosa. PPEF and CCCP together reduced bacterial load of E. coli ATCC25922 by 6 log10in neutropenic thigh infection model of balb/c mice. Present study suggests that combination therapy could be a promising antimicrobial strategy to handle MDR pathogenic strains.
authors.affiliation: Chemical Biology laboratory, Department of Chemistry, University of Delhi, Delhi, India.
authors.forename: Devapriya
authors.initials: D
authors.lastname: Sinha
authors.affiliation: Chemical Biology laboratory, Department of Chemistry, University of Delhi, Delhi, India.
authors.forename: Stuti
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Raja
authors.initials: R
authors.lastname: Singh
authors.affiliation: Chemical Biology laboratory, Department of Chemistry, University of Delhi, Delhi, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Tiwari
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Kirti
authors.initials: K
authors.lastname: Sad
authors.affiliation: Chemical Biology laboratory, Department of Chemistry, University of Delhi, Delhi, India.|Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Vibha
authors.initials: V
authors.lastname: Tandon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D006690:Bisbenzimidazole / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D048168:Escherichia coli K12 / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D019450:Genes, MDR / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D013848:Thigh / Q000382:microbiology / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D006835:Hydrazones; C070053:carbonyl 3-chlorophenylhydrazone; D004264:DNA Topoisomerases, Type I; D006690:Bisbenzimidazole