Canonical and non-canonical antibiotic resistance

Mtb is naturally resistant to many antibiotics, presumably due to its special cell wall structure and metabolic enzymes. However, for those drugs to which Mtb is not intrinsically resistant, it swiftly explores mechanisms to hamper their efficacy. Canonical drug resistance is characterized by the ability of bacteria to continue growth in the presence of antibiotics, while non-canonical drug resistance refers to more complicated mechanisms that Mtb evolves in clinical settings, where the within-host environment encountered by Mtb is more dynamic and complex, influenced by antibiotics, nutrient availability, and immune response. Characterized non-canonical resistance mechanisms in Mtb include drug tolerance and antibiotic resilience (we recently characterized). These clinically evolved, non-canonical mechanisms are important because they are significantly associated with treatment failures of patients who were "drug-sensitive" by canonical definition.

In this lab, we employ a "top-down" approach to study both canonical and non-canonical drug resistance mechanisms in Mtb. This approach starts with the identification of bacterial mutations under positive selection in the Mtb population, followed by the characterization of their drug phenotypes using high-throughput bacterial growth profiling systems that we recently developed. The goal is to identify bacterial mechanisms that Mtb evolves during treatment and are associated with unfavorable treatment outcomes. The mutations associated with such mechanisms will serve as diagnostic markers to improve diagnosis and therapeutics.