Exploration of Combinatorial Therapy for Gram Negative Bacteria such as Escherichia coli

Antibiotic resistance is certainly a worldwide concern, which presents tremendous challenge and threat to public health management of infectious diseases. The development of new drugs has become a declining strategy to combat resistance, due to the protracted and circuitous nature of it, from the search of new antimicrobial agents to their approvals in clinical use. Therefore, many have turned to the rational approach of finding combinatorial therapies with existing drugs. In this thesis, I will explore combinatorial therapy for treatment of Gram-negative bacteria, such as Escherichia coli. We utilized a mutant strain, which lacks the enzyme of deoxycytidine deaminase, and showed its hypersensitivity to a variety of compounds, from specific nucleotides to several antibiotics including vancomycin. We identified the synergistic interactions between vancomycin with cytidine, and with trimethoprim. The latter led us to the discovery of the striking potency of vancomycin and trimethoprim even in the wild-type strain. This result presents valuable implication of expanding the spectrum of a Gram-positive antibiotic to the treatment of Gram-negative infections