Molecular mechanisms of antimicrobial resistance

The emergence and spread of antimicrobial resistance represent a global threat to public health. The rise of pathogens with resistance to most or all clinically approved classes of antibiotics has resulted in a dearth of treatment options in curing critical and life-threatening infections. Our research group is interested in the molecular mechanisms underlying antimicrobial resistance, to contribute to a better understanding of drug resistance - a critical prerequisite for the rational design of novel antibacterial leads of potent efficacy against highly drug-resistant superbugs.

Aminoglycoside antibiotics are rapidly bactericidal and therefore potently efficacious therapeutics with a clinical track record of nearly eight decades. A long history of clinical use, however, has also resulted in widespread resistance to aminoglycosides. A highly diverse family of aminoglycoside-modifying enzymes, for instance, have long been known to inactivate members of this drug class by means of acetylation, phosphorylation, or nucleotidylation. Unraveling the substrate specificity of select enzymes of high clinical relevance has enabled us to design novel chemical entities that evade inactivation and retain full efficacy against aminoglycoside-resistant clinical isolates.

Another mechanism of aminoglycoside resistance prevents drug binding by means of methylation of its target site, the 16S ribosomal RNA. This type of antimicrobial resistance is of particular concern because it is found to be highly prevalent in carbapenem-resistant Gram-negative bacterial pathogens, which have been ranked as a medical need of critical urgency by the World Health Organization (WHO) and the Center for Disease Control (CDC). Our long-standing expertise in the structure-activity relationship of molecular interaction between aminoglycoside antibiotics and RNA nucleotides has facilitated the discovery and further optimization of chemical scaffolds that, unlike the drugs currently in clinical use, bind with high affinity to methylated ribosomes and retain high antibacterial efficacy in vitro and in vivo.