Therapeutics: Penicillin binding protein 2a (PBP2a)

In vitro and mouse studies suggest combining three β-lactam antibiotics that allosterically bind PBP2a could help treat methicillin-resistant Staphylococcus aureus (MRSA) infection. In cultures of the MRSA N315 strain, a combination of meropenem and the generics piperacillin and tazobactam - each of which is from a different class of β-lactam antibiotics - synergistically inhibited growth with minimum inhibitory concentrations (MICs) of 2 μg/mL, with each drug allosterically binding PBP2a. In a panel of 72 clinical isolates of MRSA, the three-drug combination synergistically decreased growth compared with any of the compounds alone or in pairs. In a mouse model of MRSA N315-induced peritonitis, the combination decreased bacterial growth in blood and increased survival compared with vehicle. Next steps include IND-enabling studies of the three-drug combination...