N-(1,3,4-oxadiazol-2-yl)benzamide analogs, bacteriostatic agents against methicillin- and vancomycin-resistant bacteria

Clement Opoku-Temeng; George A Naclerio; Haroon Mohammad; Neetu Dayal; Nader S Abutaleb; Mohamed N Seleem; Herman O Sintim

doi:10.1016/j.ejmech.2018.06.023

N-(1,3,4-oxadiazol-2-yl)benzamide analogs, bacteriostatic agents against methicillin- and vancomycin-resistant bacteria

Eur J Med Chem. 2018 Jul 15:155:797-805. doi: 10.1016/j.ejmech.2018.06.023. Epub 2018 Jun 15.

Authors

Clement Opoku-Temeng¹, George A Naclerio², Haroon Mohammad³, Neetu Dayal², Nader S Abutaleb³, Mohamed N Seleem³, Herman O Sintim⁴

Affiliations

¹ Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA; Graduate Program in Biochemistry, University of Maryland, College Park, MD, 20742, USA.
² Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA.
³ Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, N47907, USA.
⁴ Chemistry Department, Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA. Electronic address: [email protected].

PMID: 29957525
DOI: 10.1016/j.ejmech.2018.06.023

Abstract

Various reports of multidrug-resistant bacteria that are immune to all available FDA-approved drugs demand the development of novel chemical scaffolds as antibiotics. From screening a chemical library, we identified compounds with antibacterial activity. The most potent compounds, F6-5 and F6, inhibited growth of various drug-resistant Gram-positive bacterial pathogens at concentrations ranging from 1 μg/mL to 2 μg/mL. Both compounds were active against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate and vancomycin-resistant S. aureus (VISA and VRSA respectively) and vancomycin-resistant Enterococcus faecalis (VRE). Resistance generation experiments revealed that MRSA could develop resistance to the antibiotic ciprofloxacin but not to F6. Excitingly, F6 was found to be non-toxic against mammalian cells. In a mouse skin wound infection model, F6 was equipotent to the antibiotic fusidic acid in reducing MRSA burden.

Keywords: Antibiotic resistance; Bacteriostatic; Multidrug-resistant bacteria.

MeSH terms

Animals
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Resistance, Bacterial / drug effects*
Enterococcus faecalis / drug effects*
Gram-Positive Bacterial Infections / drug therapy*
Gram-Positive Bacterial Infections / microbiology
Methicillin / chemistry
Methicillin / pharmacology
Mice
Microbial Sensitivity Tests
Molecular Structure
Skin Diseases, Bacterial / drug therapy
Skin Diseases, Bacterial / microbiology
Staphylococcus aureus / drug effects*
Structure-Activity Relationship
Vancomycin / chemistry
Vancomycin / pharmacology
Wound Infection / drug therapy
Wound Infection / microbiology

Substances

Anti-Bacterial Agents
Benzamides
Vancomycin
Methicillin