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Comparative Studies to Uncover Further Mechanisms of Action of N-(1,3,4-oxadiazol-2-yl)benzamide Containing Antibacterial Agents

ABSTRACT: Drug-resistant bacterial pathogens still cause high levels mortality annually despite the availability of many antibiotics. Staphylococcus aureus (MRSA) is especially problematic and the rise in resistance to front line treatments like vancomycin and linezolid calls for new chemical modalities to treat chronic and relapsing S, aureus infections. Halogenated N-(1,3,4-oxadiazol-2-yl)benzamides are interesting class of antimicrobial agents, which have been described by multiple groups to be effective against different bacterial pathogens. The modes of action of a few N-(1,3,4-oxadiazol-2-yl)benzamides have been elucidated. For example, oxadiazoles KKL-35 and MBX-4132, have been described as inhibitors of trans-translation (a ribosome rescue pathway) while HSGN-94 was shown to inhibit lipoteichoic acid. However other similarly halogenated N-(1,3,4-oxadiazol-2-yl)benzamides neither inhibit trans-translation nor LTA but are potent antimicrobial agents. For example, HSGN-220, -218, and -144 are N-(1,3,4-oxadiazol-2-yl)benzamides that are modified with OCF3, SCF3 or SF5, and have remarkable minimum inhibitory concentrations (MICs) ranging from 1 to 0.06 microgram per mL against MRSA clinical isolates and show a low propensity to resistance to MRSA over 30 days. The mechanism of action (MOA) of these highly potent oxadiazoles is however unknown. To provide insights into how these halogenated N-(1,3,4-oxadiazol-2-yl)benzamides inhibit bacterial growth, we performed global proteomics and RNA expression analysis of some essential genes of S. aureus treated with HSGN-220, -218, and -144. These studies revealed that the oxadiazoles HSGN-220, -218, and -144 are multi-action antibiotics that regulate menaquinone biosynthesis and other essential proteins like DnaX, Pol IIIC, BirA, LexA, and DnaC. In addition, these halogenated N-(1,3,4-oxadiazol-2-yl)benzamides were able to depolarize bacterial membranes and regulate siderophore biosynthesis and heme regulation. Iron starvation appears to be part of the MOA that led to bacterial killing. This study demonstrates that N-(1,3,4-oxadiazol-2-yl)benzamides are indeed privileged scaffolds for the development of antibacterial agents and that subtle modifications lead to changes to MOA.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Staphylococcus Aureus Subsp. Aureus (ncbitaxon:46170)

SUBMITTER: Dr. Herman O. Sintim

PROVIDER: MSV000088343 | MassIVE | Wed Nov 10 10:09:00 GMT 2021

REPOSITORIES: MassIVE

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Comparative Studies to Uncover Further Mechanisms of Action of N-(1,3,4-oxadiazol-2-yl)benzamide Containing Antibacterial Agents

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