Bioorganic Approaches Toward Novel Antimicrobial Agents Against Gram-Negative Bacteria

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Principle Investigator/Program Director (Last, first, middle): Townsend, Steven D. Parent Grant Summary/Abstract: Multi-drug resistant (MDR) Gram-negative bacterial infections are an ongoing challenge to public health. Indeed, 4 of the ESKAPE pathogens recently highlighted as responsible for the majority of hospital acquired infections are Gram-negative pathogens. Although it is clear that novel antibiotics for Gram-negative infections are desperately needed, there has been minimal progress in this regard, and it has been over five decades since a new class of drugs have been introduced for Gram-negative bacteria. The development of new antibiotics to treat these pathogens is complicated by the fact that Gram-negative bacteria have an impenetrable membrane that confers intrinsic resistance to antimicrobial agents. The broad objective of this program is to study glycoconjugates to combat Gram-negative pathogens. We have made two major discoveries that suggests human milk oligosaccharides (HMOs) may be transformative in this regard. First, HMOs cause major changes to the behavior of bacteria, with strong effects on growth and the formation of biofilms, architectures that aid in bacterial survival. We have also observed that HMOs function as potent adjuvants, potentiating the activity of intracellular-targeting antibiotics by increasing cell permeability. These two discoveries form the foundation of the projects proposed in this application. In Project 1 we seek to characterize the impact of HMOs on Gram- negative causes of microbiome imbalance. In Project 2 we will explore HMOs in combination therapies against A. baumannii, an important Gram- negative pathogen. In Project 3 we investigate the chemistry and biochemistry of the mollemycin glycopeptides, a rare glycopeptide with antimicrobial activity against Gram-negative pathogens. While not sourced from milk, we plan to leverage our experience in human milk science to study the biochemistry of the mollemycins. A significant output of this work is a mechanistic understanding of the types of compounds that can enter Gram-negative bacteria. Supplement Abstract: The aminoglycoside antibiotics (AGAs) are potent broad-spectrum antibiotics that show excellence activity against aerobic, gram-negative pathogens. AGAs are limited by significant side effects, one of which is ototoxicity or AGA‐induced permanent hearing loss. Ototoxicity affects ca. 20% of the patient population. Nephrotoxicity, or the rapid erosion of kidney function is also a key side effect. Lastly, and perhaps unexpectedly, resistance evolution is problematic in AGA usage. This proposal focuses on the synthesis and biological evaluation of novel aminoglycoside derivatives against gram-negative ESKAPE pathogens, a family of multidrug resistant bacteria. Synthetic AGAs will undergo screening for inhibition of bacterial and eukaryotic ribosomes, representative of antibacterial activity and toxicity, respectively. The results of these assays will be used to inform the design and synthesis of next generation AGAs. The goal of the study is to deliver a set of validated advanced AGAs that display broad and potent antibiotic activity against wild type and multidrug resistant gram-negative bacteria, with much reduced toxicity, suitable for future development.