Expanded Screening Leads To New Class Of Antibiotics

Scientists at Pfizer are reporting a new class of antibiotics that can do battle against pathogenic gram-negative bacteria such as Haemophilus influenzae, which causes pneumonia and bacterial meningitis (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0811275106). The pyridopyrimidine-based antimicrobials selectively foil an enzyme called biotin carboxylase, which is required to build a bacterium’s essential fatty acids. The nanomolar inhibitor shown, which is active in vitro and in mice, was developed by a 30-member research team led by J. Richard Miller, Steve Dunham, and Igor Mochalkin. The researchers also report their unusual approach to finding the antibiotics. When picking bacterial proteins to target with drug screens, industry scientists normally steer clear of bacterial proteins that resemble human proteins to avoid possible patient side effects. But given the dearth of new antibiotic drug leads, the Pfizer scientists believe that screening all possible bacterial proteins—even ones that are similar to human versions—is a more sweeping strategy. They argue that pharmaceutical compound libraries contain molecules primarily designed for people, thus humanlike bacterial proteins should receive more hits. Chemists can then sidestep patient side effects by tweaking the structures using lead-optimization tools.