In a recent JACS publication a team from the University of Notre Dame present us with a new class of non-β-lactam inhibitors of the penicillin binding protein PBP2a, these compounds are oxadiazoles 1 & 2.
They were identified by in silico screening of 1.2 million compounds from the ZINC database complexed to the x-ray structure of the PBP2a from methicillin-resistant Staphlococcus aureus (MRSA). Some 50 top hits were obtained and further analysed, out of which 29 were obtained by synthesis or purchase for anti-bacterial screening against those bacteria commonly causing nosocomial infections. Twenty-nine from 1.2 million! The oxadiazole where R = F was identified as a weak inhibitor of S. aureus and E. faecium. The group prepared a library of 370 compounds based on the structure above and screened the compounds against clinically relevant micro-organisms. Three compounds emerged from this study and were evaluated for oral bioavailability from which compound 1 (R = OH) was found to be optimal in most respects.
These oxadiazoles are easily synthesised in a 6 step synthesis (4 in the main chain, 3 in a side chain) in good overall yield starting from 4-iodobenzonitrile, 4-(trifluoromethyl)phenol under Cu catalysis to give the di-benzyl ether 3.
Conversion of 3 to the products 1 & 2 is simple, treatment with hydroxyl amine, then reaction with the acid chloride of a (4-trialkylsilyloxy)benzoic acid and removal of the silyl group delivers compound 1. This compound has an ED50 of 40 mg/kg i.v and 44 mg/kg orally. It is highly bioavailable.
The mechanism of action was investigated by a variety of means using modified DNA, RNA protein of peptidoglycans, by methods which I am not competent to describe. The gene encoding PBP2a was cloned and purified and compound 1 evaluated by a spectrophotometric method. Compound 1 inhibited the PBP2a at an IC50 of 4μg/mL. An x-ray structure of the oxadiazole bound to PBP2a were until now, not successful. Perhaps the crystalline sponge method would be of value here?
This work represents a significant breakthrough in the search for novel antibiotics, especially against Gramm-positive bacteria. Of note is the oral bioavailability of the compounds and their ability to disrupt an important enzyme involved in bacterial cell wall synthesis. This is another advance in the fight against β-lactam resistant bacteria. I sure hope this is picked up by the pharma industry and developed further and rapidly. Especially attractive is the simple synthetic route.
To end up with 2 compounds from 1.2 million indicates just how difficult the search for new antibiotics is and this team have done a tremendous job.
