Mechanistic Studies and In Vivo Efficacy of an Oxadiazole-Containing Antibiotic

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) infections are still difficult to treat, despite the availability of many FDA-approved antibiotics. Thus, new compound scaffolds are still needed to treat MRSA. The oxadiazole-containing compound, HSGN-94, has been shown to reduce lipoteichoic acid (LTA) in S. aureus, but the mechanism that accounts for LTA biosynthesis inhibition remains uncharacterized. Herein, we report the elucidation of the mechanism by which HSGN-94 inhibits LTA biosynthesis via utilization of global proteomics, activity-based protein profiling, and lipid analysis via multiple reaction monitoring (MRM). Our data suggest that HSGN-94 inhibits LTA biosynthesis via direct binding to PgcA and downregulation of PgsA. We further show that HSGN-94 reduces the MRSA load in skin infection (mouse) and decreases pro-inflammatory cytokines in MRSA-infected wounds. Collectively, HSGN-94 merits further consideration as a potential drug for staphylococcal infections.

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

“…Fractions containing the product were identified by TLC and pooled, and the solvent was removed in vacuo. 1 H, 13 C, and 19 F NMR spectra were recorded on a Bruker Ascend 500, Bruker Ultrashield 400, or Bruker Fourier 300 spectrometer at 500, 400, and 300 MHz, respectively, for 1 H NMR; at 125, 100, and 75 MHz for 13 C NMR; and at 470 and 376 MHz, respectively, for 19 F NMR. Spectra were calibrated to the deuterated solvent reference peak in 1 H NMR and 13 C NMR.…”

“…5b was prepared according to general procedure 2 from 4b (1.3 g, 4.7 mmol) and 1 M aqueous NaOH (25 mL) and obtained as a brown amorphous solid (1.0 g, 43%). TLC [5% methanol in dichloromethane]: R f : 0.51; 1 H NMR (400 MHz, DMSO-d 6 ): 8.45 (1H, d, J = 9.5 Hz), 8.16 (1H, d, J = 9.0 Hz), 7.60−7.52 (2H, m), 7.39 (1H, dd, J = 9.5, 2.9 Hz), 6.85 (2H, s), 5.38 (2H, s), 3.92 (3H, s); 13 4.2.1.10. 2-Amino-5-phenyl-1,3,4-oxadiazole (7a).…”

“…Considerable effort is being directed at developing multidrug efflux pump inhibitors for the treatment of Gram-negative infections; 60 the discovery that 1771 and 13 are active against multidrug-resistant Gramnegative pathogens holds promise for future combinatorial therapy with efflux pump inhibitors. In addition, we and others 12 have observed limited resistance development against 1771 (Figure S2) and similar compounds 13 following extensive in vitro serial passage, which may be explained if 1771 and related molecules inhibit multiple targets, preventing the rapid emergence of resistance.…”

Menthone Exerts its Antimicrobial Activity Against Methicillin Resistant Staphylococcus aureus by Affecting Cell Membrane Properties and Lipid Profile

“… 59 The oxadiazole-containing compound HSGN-94 could inhibit the biosynthesis of LTA in S. aureus by binding to PgcA and downregulation of PgsA. 60 , 61 Brevibacillin, one of the natural antimicrobial agents, could disrupt cytoplasmic membrane of S. aureus by binding to LTA. 62 Similar lipid biosynthesis scheme has been designed for S. aureus in previous studies.…”

Recent Advances in the Synthesis and Medicinal Chemistry of SF5 and SF4Cl Compounds

“…Sintim and co-workers demonstrated that incorporation of the SF 5 group into oxadiazoles can enhance the antibacterial properties of these compounds. 50 The authors discovered that the SF 5 containing (1,3,4-oxadiazol-2-yl)benzamide 14 (Scheme 58 ) exhibits a wide spectrum of activities against an extensive panel of resistant Gram-positive bacterial strains, displaying MIC values higher than those of the non-substituted analogue. The SF 5 derivative was synthesized in modest yields in one step via amide coupling between para-SF 5 -benzoic acid and 2-aminooxadiazole.…”