Using deep mutational scanning to identify the determinants of antibiotic resistance

Abstract

Current drug discovery platforms have proven incapable of supplying enough new antibiotic types to meet the challenge of rapidly developing clinical resistances. New techniques that specifically incorporate potential resistance adaptations during design are necessary. In cases of known specific resistance mechanisms, a biophysical approach may allow rational development of existing drugs that escape resistance. In this work, we use deep mutational scanning (DMS), a next-generation sequencing-based technique that reports on the site-specific fitness effects of mutations across an entire protein, to investigate the contribution of Virginiamycin acetyltransferase (VatD) to several streptogramin analogues.