Targeting Multidrug Resistant Eskape Pathogens Alternative Strategies and Novel Approaches

Abstract

Over the past few decades, multidrug-resistant (MDR) Gram-negative bacteria that are resistant to three or more classes of antibiotics have become more prominent and today, we even find infections caused by extremely-drug resistant or XDR (resistant to all but one antibiotic class) and pan-drug resistant (PDR) (resistant to all available antibiotics) bacteria. With the ability to overcome host immunity and resist antibiotics at both the intrinsic and adaptive level, Gram-negative pathogens are the perfect superbugs . Systematic analysis of global antimicrobial resistance (AMR) data from 2019, credits only six bacterial pathogens responsible for 3.57 million of a total 4.95 million deaths associated with antimicrobial resistance globally (Murray et al. 2022). Two of these top six pathogens are the Gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter baumannii, which are notorious for causing a variety of infections in humans due to their arsenal of virulence factors and survival tactics. It is therefore imperative to identify alternative strategies to target MDR Gram-negative infections. The current antibiotic resistance crisis leaves clinicians with limited options for therapy as MDR infections become essentially untreatable . Additionally, consistent exposure to stressors (like antibiotics) in chronic infections can often lead to hypermutability and survival phenotypes that may result in more persistent infections The present study was carried out to identify alternatives to traditional antibiotic regimen for the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii infections. Innovative strategies that utilize bacteriophages, target virulence, and sensitize the pathogen to the host innate immune response are optimal as they spare the normal microbiome, provide less selective pressure for antibiotic resistance and could even be used in concert with antibiotics for increased efficacy. This is addressed through the four objectives of this thesis: (attached)