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 E. 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 inhibition of vital respiratory enzymes in the bacterial inner membrane represents one of the secondary modes of action for polymyxins.

The polymyxin B-induced transcriptomic response of a clinical, multidrug-resistant Klebsiella pneumoniae involves multiple regulatory elements and intracellular targets

“…Interestingly, a secondary mode of action for PB has been described and involves inhibitory activity against NDH-2, a vital respiratory enzyme in the bacterial inner membrane [5]. This would lead to the activation of genes involved in the response to decreased oxidative power within the cell, including arcB , as we have observed.…”

“…The control between these different metabolic modes lies on the repression and derepression of the corresponding enzymes [34, 35]. Recent studies report that polymyxin B inhibits the activity of NDH-2 in the bacterial inner membrane of K. pneumoniae , E. coli and A. baumannii [5]. Besides the type II NDH-2 that is encoded by the ndh gene, these bacteria produce another type of NADH-quinone oxidoreductase for the respiratory chain, namely the type I (NDH-1) encoded by 13 tandemly arranged genes ( nuoA - nuoN ) [34].…”

“…The mode of action of these drugs is also not completely elucidated, but generally involves interaction with lipopolysaccharides (LPS) located in the outer membrane of Gram-negative bacteria, competing with the calcium and magnetic ions that stabilize LPS, allowing for drug uptake to the cell interior [3]. It has been reported that PB activity may involve inhibition of vital respiratory enzymes located in the inner membrane, such as NADH-quinone oxidoreductase (NDH-2) [5], thereby hampering bacterial respiration.…”

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

“…Finally, another mode of action of the polymyxins is the inhibition of vital respiratory enzymes (inhibition of type II NADH-quinone oxidoreductases ) in the bacterial inner membrane (15).…”

Agents of Last Resort

“…12,13 A secondary antibacterial mechanism of polymyxins is thought to be via inhibition of the nicotinamide adenine dinucleotide oxidase enzyme family. This inhibitory activity has been observed in Escherichia coli, Klebsiella pneumoniae, A baumannii, 14 and Mycobacterium smegmatis. 15 …”