Oxadiazoles Attack Resistant Bacteria

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) send 278,000 people to the hospital and kill 19,000 every year in the U.S. Researchers have identified possible new weapons in the fight against MRSA: a class of compounds called oxadiazoles that inhibit a protein used by MRSA to get around penicillin-like drugs (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja500053x).

Regular S. aureus relies on four penicillin-binding proteins to construct its bacterial cell wall by synthesizing peptidoglycans. β-lactam antibiotics such as penicillin annihilate bacteria by inhibiting these proteins and disrupting cell wall construction. But MRSA is impervious to these antibiotics because it has a fifth penicillin-binding protein called PBP2a that resists the drug molecules, allowing peptidoglycan synthesis to continue, says Mayland Chang of the University of Notre Dame.

In hopes of discovering new inhibitors of PBP2a, Chang and colleagues screened 1.2 million compounds with computer programs that assessed how well each molecule fit into the active site of the PBP2a crystal structure. The researchers then took the top-scoring compounds and used them as the starting point to find molecules that inhibited the growth of resistant bacteria in cultures. After two rounds of lab testing, they selected the three most lethal compounds for mouse studies.

The researchers gave a lethal dose of MRSA to mice, followed by a dose of the experimental compounds. The most effective compound saved half the mice with an oral dose of 44 mg per kg of animal mass—not as potent as antibiotics that treat MRSA such as vancomycin but still a reasonable dosage, Chang says. Moreover, 100% of the compound ingested by the rodents reached their circulatory system, a nice property, Chang says, considering vancomycin must be injected to be effective.

Chang next plans to continue to tweak the structures of oxadiazoles to improve their antibacterial activity.