Researchers at Duke University and the University of Connecticut have made a significant discovery in the fight against methicillin-resistant Staphylococcus aureus (MRSA), a bacterial infection that has become resistant to most antibiotics used to treat regular staph infections.
The team has published their findings in PLOS Computational Biology, where they discuss how a small mutation in the dihydrofolate reductase (DHFR) enzyme can impact the efficacy of drugs designed to inhibit it.
The DHFR enzyme is targeted by antibiotics in the treatment of MRSA, with drugs that inhibit it working in a similar way to locks and keys. These drugs bind to enzymes in MRSA, but their effectiveness can be compromised by a mutation that changes the three-dimensional structure of the enzyme, effectively altering the lock. The F98Y mutation, which changes a phenylalanine to a tyrosine at the 98th amino acid in DHFR, is a well-known resistance mutation that causes drugs to lose their effectiveness.
While attempting to predict this mutation using a computational structure-based protein design program, researchers discovered something unexpected. The crystallographer had flipped the chirality, or made a mirror image, of the NADPH cofactor in order to get a better fit for the structure of the F98Y mutant. This “flipped” chemical species, which can exist both in experimental conditions and in vivo, appears to work in conjunction with the enzyme mutation to evade drug inhibitors.
This “chiral evasion” changes the structural basis for resistance, but it also provides researchers with the information they need to create a better key, or drug inhibitor, by taking the flipped chirality into account. Using this knowledge, the team was able to improve the predictions of their program and closely match experimental measurements of inhibitor potency.