In the fight against harmful bacteria, the last line of defense is beginning to fail. The only drugs that work against certain multidrug-resistant microbes are polymyxins, but some pathogens are beginning to develop resistance to these last-resort therapeutics. Using computer modeling, researchers designed polymyxin-like molecules that can overcome that resistance and serve as a first step toward new medications (ACS Chem. Biol. 2014, DOI: 10.1021/cb500080r).
Polymyxins are natural lipopeptides that bind to lipid A, a component of the cell wall of gram-negative bacteria. The compounds work by disrupting ionic and hydrophobic interactions in the cell envelope, leading to a microbe’s demise, says Kade D. Roberts, a senior research scientist in Jian Li’s laboratory at Monash University, in Australia. When faced with a bacterial infection that doesn’t respond to any other treatment, doctors are left with prescribing a polymyxin. But now, polymyxin-resistant bacteria have evolved with altered forms of lipid A.
Based on a structural model of polymyxin bound to the resistant version of lipid A developed by team member Tony Velkov, the researchers concluded that resistance stems from changes in the lipid that affect hydrophobic interactions with the drug. They used that information to look for modifications that could stabilize the drug-lipid complex and then synthesize a series of new polymyxin-like molecules.
To test their next-generation polymyxins, the researchers grew polymyxin-resistant strains of Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Their best compounds kill the bacteria at concentrations as low as 2 mg/L. “It’s a good starting point,” Roberts says, but the compounds aren’t ready for the clinic yet. The researchers are now working on additional polymyxins with greater potency and improved drug properties.