To defeat multidrug-resistant superbugs, bacterial defenses must be confronted wherever they may emerge, from basic genetic mutations in a laboratory, to complex real-world transmission in hospital rooms. A new trio of studies published in Antimicrobial Agents and Chemotherapy and researched by the laboratory of Barry N. Kreiswirth, Ph.D., at the Hackensack Meridian Center for Discovery and Innovation (CDI) demonstrates how an integrated approach might yet expose and overcome these diverse survival mechanisms.
The Kreiswirth Lab continues to focus on different aspects of antimicrobial resistance (AMR) and Kreiswirth himself has driven or collaborated on these AAC studies.
“These studies show collectively how we are tracking and better understanding the many forms of drug resistance that bacterial pathogens evolve, given the opportunity,” said Barry Kreiswirth, Ph.D., member of the CDI and professor at the Hackensack Meridian School of Medicine.
The three peer-reviewed papers, published together in the American Society for Microbiology journal, explore bacterial resistance across three distinct dimensions.
In the first paper, the team used high-density transposon sequencing (TnSeq) to map genes governing susceptibility in carbapenem-resistant Klebsiella pneumoniae. The scientists, led by Zhichen Zhu, Ph.D., Liang Chen, Ph.D., of the University at Buffalo, and Kreiswirth, discovered that when superbugs alter their outer surface to evade viral phages, they pay an evolutionary price: losing these surface receptors re-sensitizes the bacteria to last-line antibiotics like meropenem, colistin, and cefiderocol.
The second publication shows how cefiderocol - a novel siderophore cephalosporin that exploits bacterial iron-uptake channels - can be evaded by so-called “superbugs.” The team identified a multi-layered defense network involving cell envelope homeostasis and blaKPC-3 β-lactamases. Deleting blaKPC-3 in resistant strains reduced drug minimum inhibitory concentrations fourfold, showing how low intracellular drug levels allow even modest enzyme activity to drive high-level resistance. The lead authors are Kevin J. Rome, Ph.D., Austin J. Terlecky, and Kreiswirth.
The third documented how the CDI team and colleagues tracked 159 acute leukemia and myelodysplastic syndrome patients undergoing chemotherapy. The researchers found that 20 percent of patients colonized with extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) developed matching bloodstream infections during neutropenia. Whole-genome sequencing confirmed a 100 percent match between colonizing and bloodstream strains, proving that targeted screening can effectively guide prophylactic antibiotics, while preventing unnecessary overuse. This prospective study was led by Kate Stoeckle, M.D., Michael J. Satlin, M.D., Lars F. Westblade, Ph.D., all of Weill-Cornell Medicine, Chen, and Kreiswirth.
“By bridging molecular genetics, genomics, and clinical epidemiology, Barry Kreiswirth and his lab continue to uncover the underlying rules of bacterial survival - which are pointing the way toward better clinical outcomes,” said David Perlin, chief scientific officer and executive vice president, of the CDI.