Compound may make resistant TB antibiotic-susceptible

A new compound of C-capped dipeptides, called BU-005, has been found to circumvent a family of drug-efflux pumps that bacteria use to recognize and expel drugs that have breached their membranes.
By inhibiting the efflux pumps, gram-positive bacteria such as dangerous MRSA and tuberculosis strains may be susceptible to drugs again. This would allow scientists to develop inhibitors of efflux pumps instead of developing entirely new kinds of antibacterial drugs.
"(Efflux pumps turn) out to be a real problem in clinical settings, especially when a bacterial pathogen acquires a gene encoding an efflux pump that acts on multiple antibiotics," Jason Sello, an assistant professor of chemistry at Brown University, said. "In the worst case scenario, a bacterium can go from being drug-susceptible to resistant to five or six different drugs by acquiring a single gene."
A Brown University team used an Ugi reaction to prepare dozens of different C-capped dipeptides. The team then assessed each compound's ability to block two efflux pumps in the bacterium Streptomyces coelicolor, a relative of Mycobacterium tuberculosis that resists chloramphenicol, one of the oldest antibacterial drugs. The group discovered BU-005 to be the most effective.
"Our findings that C-capped dipeptides inhibit efflux pumps in both gram-positive and gram-negative bacteria should reinvigorate interest in these compounds," Sello said. "Moreover, our simplified synthetic route should make the medicinal chemistry on this class of compounds much simpler."