The speed at which bacteria evolve and develop resistance to first-line antibiotics continues to outpace conventional drug discovery efforts.
Drug-resistant bacteria are now responsible for almost two million infections annually in the U.S. alone, and more than 23,000 deaths, according to statistics published by the Centers for Disease Control and Prevention (CDC).
Moreover, the increase in incidence of drug-resistant infections has eroded the utility of many classes of antibiotics.
Despite this, recent advances in the field of antibiotic resistance – particularly the molecular mechanisms underpinning this phenomenon – have given way to unprecedented insight into not only the evolution of bacteria, but how they manage to evade antimicrobial compounds.
Researchers from McMaster University, along with colleagues from the University of Toronto, have added to this body of knowledge by revealing structural and molecular insights into how a new class of antibiotic resistance enzyme inactivates a first-line drug against tuberculosis (TB).
In a study published in the journal Nature Communications, researchers describe the molecular mechanism that causes rifampin phosphotransferase (RPH) – an enzyme widespread in environmental and pathogenic bacteria – to confer high-level resistance to rifampin.
The collaborative effort first led the researchers to crystallize RPH to determine its structure, which later identified three distinct domains: two substrate-binding domains and a smaller phosphate-carrying domain.
Further analysis of the enzyme’s structure revealed that the smaller domain is capable of swinging between its larger counterparts during catalysis, allowing for the phosphorylation, or inactivation, of rifampin.
“This is really quite a complex mechanism for antibiotic resistance,” says Dr. Georgina Cox, a postdoctoral fellow at the Michael G. DeGroote Institute for Infectious Disease Research and an author of the study.
“I really think it highlights how intricate and sophisticated antibiotic resistance really is.”
Such an enzymatically complex mechanism of antibiotic resistance, the authors suggest, “augments the spectrum of strategies used by bacteria to evade antimicrobial compounds.”
The authors go onto conclude that an in-depth understanding of the structural and molecular basis underlying rifampin inactivation by RPHs will further clarify this complex catalytic mechanism, eventually leading to the generation of rifampin analogues that are not susceptible to inactivation.
“Resistance is more complicated than we originally thought,” adds Dr. Cox. “But if we are able to anticipate these resistance elements before they actually become a problem, we will be better prepared for when they reach the clinic.”