Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function

Abstract

The lipoteichoic acid (LTA) biosynthesis pathway has emerged as a promising antimicrobial therapeutic target. Previous studies identified the 1,3,4 oxadiazole compound 1771 as an LTA inhibitor with activity against Gram-positive pathogens. We have succeeded in making six 1771 derivatives and, through subsequent hit validation, identified the incorporation of a pentafluorosulfanyl substituent as central in enhancing activity. Our newly described derivative, compound 13, showed a 16- to 32-fold increase in activity compared to 1771 when tested against a cohort of multidrug-resistant Staphylococcus aureus strains while simultaneously exhibiting an improved toxicity profile against mammalian cells. Molecular techniques were employed in which the assumed target, lipoteichoic acid synthase (LtaS), was both deleted and overexpressed. Neither deletion nor overexpression of LtaS altered 1771 or compound 13 susceptibility; however, overexpression of LtaS increased the MIC of Congo red, a previously identified LtaS inhibitor. These data were further supported by comparing the docking poses of 1771 and derivatives in the LtaS active site, which indicated the possibility of an additional target(s). Finally, we show that both 1771 and compound 13 have activity that is independent of LtaS, extending to cover Gram-negative species if the outer membrane is first permeabilized, challenging the classification that these compounds are strict LtaS inhibitors.

A Novel Antimicrobial Mechanism of Azalomycin F Acting on Lipoteichoic Acid Synthase and Cell Envelope

“…More importantly, it was further confirmed by the fact that azalomycin F-induced S. aureus lysis can be can prevented by the cellular LTA [ 19 ]. This evidence is very crucial for the judgement of whether a compound is an LtaS inhibitor or not, since some compounds like compound 1171 and its derivatives were eventually proved to be not LtaS inhibitors except for Congo red, which was mainly because neither the deletion nor overexpression of LtaS altered the susceptibility of S. aureus to them [ 11 ].…”

“…However, there are no other LtaS inhibitors reported to date besides compound 1771, dye Congo red and compound 4 [ 8 , 9 , 10 ]: especially none reported from natural products. As mentioned in the Introduction section, except for dye Congo red, compound 1771 and its derivatives [ 11 ], together with two compounds reported by Muscato, et al [ 12 ], were proved to not be LtaS inhibitors. Thereby, azalomycin F can be considered as the first natural LtaS inhibitor, and this research can provide an important reference for the discovery of more potent LtaS inhibitors to treat S. aureus infection.…”

“…However, Vickery et al had confirmed that compound 1771 did not inhibit LtaS directly and suggested that it probably inhibited another enzyme required for polymer production and had a more general toxicity [8]. This was also supported by the conclusion reported by Douglas et al based on the critical facts that neither the deletion nor overexpression of LtaS alter the susceptibility of S. aureus to compounds 1771 and its derivative 13, while the overexpression of LtaS can alter that to Congo red [11]. Muscato et al discovered two inhibitors of the glycosyltransferase UgtP, which assembles the LTA glycolipid anchoring on the S. aureus cell membrane [12].…”

Syntheses, reactivity, and biological applications of coumarins

“…Multidrug-resistant (MDR) bacterial infections represent a global emergency leading to the increase of the mortality rate due to the inefficacy of currently used antibiotics for the treatment of common infections ( Serpi et al, 2023 ). In the last decade, several efforts have been made towards the discovery of broad spectrum antibacterials ( Douglas et al, 2023 ). In this context, the coumarin moiety emerged as a promising scaffold for the design of potential antibacterial agents.…”