DISRUPTING BACTERIAL DEFENSES: POTENTIATION OF CONVENTIONAL THERAPEUTICS AND DEVELOPMENT OF NEXT-GENERATION DRUG TARGETS

Abstract

The widespread use of antibiotics and other antimicrobial compounds has been a boon to human health and saved countless lives over the last century. This has coincided with the emergence of antimicrobial resistance (AMR) within populations of these microbes, which is increasingly making the treatment of the infections they cause more difficult. In some cases, pathogenic strains have emerged which are resistant to all antibiotics available, meaning the infections are untreatable. The increasing occurrence of AMR within pathogens necessitates the development of new therapies to combat this; alternatively, new approaches can be developed which make use of current therapeutic agents, in turn enabling us to use otherwise ineffective treatment options.One such strategy is the use of a potentiator molecule, which can restore susceptibility to an antibiotic in otherwise resistant organisms. The Rice lab proposes the use of branched polyethylenimine (BPEI), which can permeabilize bacterial membranes and restore susceptibility to a wide variety of antibiotics in previously resistant Gram-positive and -negative bacteria. In Chapter Two, we explore the consequences of bacterial resistance to BPEI in the pathogen Pseudomonas aeruginosa, which results in increased susceptibility to aminoglycoside antibiotics in the BPEI-resistant strains. We also report on the development of a collagen sponge in Chapter Three for the delivery of BPEI against biofilms of P. aeruginosa. Another strategy to combat AMR is to develop new targets for antimicrobial agents. Ideally, these novel targets will be widely present within bacteria but not our own cells. In the Rajan lab, we used a bioinformatic approach for protein motif analysis to identify motifs in the Cas9 sequence which are only present in pathogenic bacteria. This presents a new avenue of research to begin identifying targets for new antimicrobial agents.