title: A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity.
abstract: Polymyxin B and colistin were examined for their ability to inhibit the type II NADH-quinone oxidoreductases (NDH-2) of three species of Gram-negative bacteria. Polymyxin B and colistin inhibited the NDH-2 activity in preparations from all of the isolates in a concentration-dependent manner. The mechanism of NDH-2 inhibition by polymyxin B was investigated in detail with Escherichia coli inner membrane preparations and conformed to a mixed inhibition model with respect to ubiquinone-1 and a non-competitive inhibition model with respect to NADH. These suggest that the inhibition of vital respiratory enzymes in the bacterial inner membrane represents one of the secondary modes of action for polymyxins.
authors.affiliation: 1] Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia [2] Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.
authors.forename: Zakuan Z
authors.initials: ZZ
authors.lastname: Deris
authors.affiliation: Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Jesmin
authors.initials: J
authors.lastname: Akter
authors.affiliation: Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Sivashangarie
authors.initials: S
authors.lastname: Sivanesan
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Kade D
authors.initials: KD
authors.lastname: Roberts
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.affiliation: Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.affiliation: Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000201:enzymology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D003091:Colistin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D009243:NAD / Q000037:antagonists & inhibitors; D011112:Polymyxin B / Q000494:pharmacology*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D014451:Ubiquinone / Q000037:antagonists & inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D009243:NAD; D014451:Ubiquinone; C004691:colistinmethanesulfonic acid; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D011112:Polymyxin B; D003091:Colistin