Combination Antibacterial Therapy against β-lactam Drug Resistance

Abstract

The β-lactam antibiotics have been the primary therapeutic treatments to combat common bacterial infections. However, the emergence of β-lactamase producing multi-drug resistant bacterial pathogens has become a major problem for public health. To address this problem, antibiotics are administered in combination with β-lactamase inhibitors to treat drug resistance pathogens. To date, there are only four β-lactamase inhibitors approved for combination therapy by the US Food and Drug Administration (FDA). With the continuing emergence of drug-resistant β-lactamase mutants worldwide, there is an urgent need to expand the repertoire of β-lactamase inhibitors for combination therapy. The major objective of my research was to identify a new class of β-lactamase inhibitors that can restore β-lactam antibiotics activity and use them for combination antibacterial therapy. I successfully established the use of sulfonyl oxadiazole and 1-hydroxypyridine-2-thiones-6-carboxylic acid as two novel classes of β-lactamase inhibitors against serine and metallo β-lactamases respectively that can effectively restore β-lactam antibiotic activity. Based on a cell-based and biochemical study, I further demonstrated the promising therapeutic potential of these compounds which were subsequently disclosed in two patent applications.