Inhibition of the Staphylococcus aureusNADPH-dependent Enoyl-Acyl Carrier Protein Reductase by Triclosan and Hexachlorophene

Abstract

Enoyl-acyl carrier protein reductase (FabI) plays a determinant role in completing cycles of elongation in type II fatty acid synthase systems and is an important target for antibacterial drugs. The FabI component of Staphylococcus aureus (saFabI) was identified, and its properties were compared with Escherichia coli FabI (ecFabI). ecFabI and saFabI had similar specific activities, and saFabI expression complemented the E. coli fabI(Ts) mutant, illustrating that the Gram-positive FabI was interchangeable with the Gram-negative FabI enzyme. However, ecFabI was specific for NADH, whereas saFabI exhibited specific and positive cooperative binding of NADPH. Triclosan and hexachlorophene inhibited both ecFabI and saFabI. The triclosanresistant ecFabI(G93V) protein was also refractory to hexachlorophene inhibition, illustrating that both drugs bind at the FabI active site. Both the introduction of a plasmid expressing the safabI gene or a missense mutation in the chromosomal safabI gene led to triclosan resistance in S. aureus; however, these strains did not exhibit cross-resistance to hexachlorophene. The replacement of the ether linkage in triclosan by a carbon bridge in hexachlorophene prevented the formation of a stable FabI-NAD(P) ؉ -drug ternary complex. Thus, the formation of this ternary complex is a key determinant of the antibacterial activity of FabI inhibitors.

Structural Elucidation of the Specificity of the Antibacterial Agent Triclosan for Malarial Enoyl Acyl Carrier Protein Reductase

“…Studies with a des-hydroxyl analog of triclosan showed a more than 10,000-fold reduced affinity for E. coli ENR and implicated a critical antibacterial role for the triclosan 2-hydroxy group (55). Moreover, it was proposed that the ether oxygen of triclosan might be critical to the formation of the ternary complex, because corresponding 2-hydroxydiphenylmethanes did not result in tight binding (59), whereas the replacement of the ether oxygen with sulfur abolished the inhibitory activity (21). Ring B of triclosan was considered to be of minor importance, because variations in this region had less effect on inhibitor activity.…”

Hand Hygiene

“…394 Recent studies suggest that this agent's antibacterial activity is attributable in large part to binding to the active site of enoylacyl carrier protein reductase. 395,396 Triclosan has a fairly broad range of antimicrobial activity ( Table I.11.7), but tends to be bacteriostatic. 48 Minimum inhibitory concentrations (MICs) range from 0.1 to 10 μg/ ml, while minimum bactericidal concentrations are 25-500 μg/ml.…”

“…433,434 Very high MICS for triclosan were reported by Sasatsu and colleagues, 438 and the description of a triclosan-resistant bacterial enzyme has raised the question of whether resistance may develop more readily to this agent than to other antiseptic agents. 396 Under laboratory conditions, bacteria with reduced susceptibility to triclosan carry crossresistance to antibiotics. 439,440 Reduced triclosan susceptibility or resistance was detected in clinical isolates of methicillinresistant S. epidermidis and in MRSA, respectively.…”

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

“…PfENR is known to be an important target for the development of antimicrobial and antiparasitic molecules (11)(12)(13)(14)(15). We have reported earlier that triclosan, a microbicide and a common additive in many household items, strongly inhibits PfENR with high potency and also exhibits slow-tight binding mechanism in presence of catechins (16,17).…”