Luke Diorio-Toth

MSTP in PhD Training

Program: Computational and Systems Biology

Current advisor: Gautam Dantas, PhD

Undergraduate university: Carnegie Mellon University, 2014

Enrollment year: 2016

Research summary
Mapping the evolutionary landscape of a novel family of tetracycline resistance enzymes

Antibiotic resistance imposes significant burden on human health and healthcare resources, so developing strategies that mitigate emerging antibiotic resistance mechanisms are critical for public health. Tetracyclines are a vital class of antibiotics, but increasing resistance threatens their efficacy. Tetracycline resistance is thought to mainly occur through antibiotic efflux and ribosomal protection. Increasingly, resistance to late-generation tetracyclines, including antibiotics of last-resort, through enzymatic inactivation is being detected in environmental and clinical samples. These enzymes, known as tetracycline destructases, are now widely recognized as a clinically-relevant resistance mechanism. Despite recent interest in these enzymes, the precise sequence requirements that distinguish them from other flavoenzymes, and enable activity towards tetracyclines is unclear. To address these gaps in knowledge, I am using a combination of bacterial genomics, synthetic biology, and molecular evolution approaches. The long-term goal for this proposal is to better understand the evolutionary origins and structural features of tetracycline destructases in order to rationally design better diagnostics and inhibitors to re-store efficacy of this vital class of antibiotics before they become a widespread cause of morbidity and mortality.

Graduate publications
Diorio-Toth L, Irum S, Potter RF, Wallace MA, Arslan M, Munir T, Andleeb S, Burnham CD, Dantas G. 2022 Genomic Surveillance of Clinical Pseudomonas aeruginosa Isolates Reveals an Additive Effect of Carbapenemase Production on Carbapenem Resistance. Microbiol Spectr, 10(3):e0076622.

Stogios PJ, Bordeleau E, Xu Z, Skarina T, Evdokimova E, Chou S, Diorio-Toth L, D’Souza AW, Patel S, Dantas G, Wright GD, Savchenko A. 2022 Structural and molecular rationale for the diversification of resistance mediated by the Antibiotic_NAT family. Commun Biol, 5(1):263.

Sukhum KV, Diorio-Toth L, Dantas G. 2019 Genomic and Metagenomic Approaches for Predictive Surveillance of Emerging Pathogens and Antibiotic Resistance. Clin Pharmacol Ther, 106(3):512-524.