Search

Clostridioides difficileis an anaerobic Gram-positive bacterium that colonizes the gut of patients treated with broad-spectrum antibiotics. The normal gut microflora prevents C. difficilecolonization; however, dysbiosis by treatment with broad-spectrum antibiotics causes recurrent C. difficileinfection (CDI) in 25% of patients. There are no fully effective antibiotics for multiple recurrent CDIs. We report herein that oxadiazole antibiotics exhibit bactericidal activity against C. difficilevegetative cells. We screened a library of 75 oxadiazoles against C. difficileATCC 43255. The findings from this collection served as the basis for the syntheses of an additional 58 analogs, which were tested against the same strain. We report a potent (MIC50= 0.5 μg/mL and MIC90= 1 μg/mL values for 101 C. difficilestrains) and narrow-spectrum oxadiazole (3-(4-(cyclopentyloxy)phenyl)-5-(4-nitro-1H-imidazol-2-yl)-1,2,4-oxadiazole; compound 57), which is not active against common gut bacteria or other tested organisms. Compound 57is selectively bactericidal against C. difficileand targets cell-wall synthesis.

We report herein the syntheses of 79 derivatives of the 4(3H)-quinazolinones and their structure–activity relationship (SAR) against methicillin-resistant Staphylococcus aureus(MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound 73((E)-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one) for further study. The compound synergized with piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically relevant mouse model of MRSA infection. The TZP combination lacks activity against MRSA, yet it synergized with compound 73to kill MRSA in a bactericidal manner. The synergy is rationalized by the ability of the quinazolinones to bind to the allosteric site of penicillin-binding protein (PBP)2a, resulting in opening of the active site, whereby the β-lactam antibiotic now is enabled to bind to the active site in its mechanism of action. The combination effectively treats MRSA infection, for which many antibiotics (including TZP) have faced clinical obsolescence.

ABSTRACTThe oxadiazole antibacterials target the bacterial cell wall and are bactericidal. We investigated the synergism of ND-421 with the commonly used β-lactams and non-β-lactam antibiotics by the checkerboard method and by time-kill assays. ND-421 synergizes well with β-lactam antibiotics, and it also exhibits a long postantibiotic effect (4.7 h). We also evaluated the in vivoefficacy of ND-421 in a murine neutropenic thigh infection model alone and in combination with oxacillin. ND-421 has in vivoefficacy by itself in a clinically relevant infection model (1.49 log10bacterial reduction for ND-321 versus 0.36 log10for linezolid with NRS119) and acts synergistically with β-lactam antibiotics in vitroand in vivo, and the combination of ND-421 with oxacillin is efficacious in a mouse neutropenic thigh methicillin-resistant Staphylococcus aureus(MRSA) infection model (1.60 log10bacterial reduction). The activity of oxacillin was potentiated in the presence of ND-421, as the strain would have been resistant to oxacillin otherwise.

The quinazolinones are a new class of antibacterials with in vivoefficacy against methicillin-resistant Staphylococcus aureus(MRSA). The quinazolinones target cell wall biosynthesis and have a unique mechanism of action by binding to the allosteric site of penicillin-binding protein 2a (PBP 2a).