Title

Towards the Understanding of Resistance Mutations in Dihydrofolate Reductase from Methicillin-resistant Staphylococcus aureus

Date of Completion

January 2011

Keywords

Biology, Microbiology|Chemistry, Biochemistry|Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections, most frequently associated with bacteremia, skin and soft tissue infections, and ventilator-assisted pneumonia. The increasing frequency of infections caused by MRSA is a global health concern not only in hospital settings, but also in the community where even healthy individuals are at risk. Resistance to therapeutics has become an increasing problem in treating MRSA. While trimethoprim-sulfamethoxazole (TMP-SMZ) is an alternative treatment for MRSA infections, resistant strains have arisen with point mutations in dihydrofolate reductase (DHFR), the validated target for TMP. Given the rapid emergence of resistance, a multi-disciplinary effort has been established to design a library of propargyl-linked inhibitors targeting DHFR from MRSA and other TMP-resistant pathogens. In parallel with this initiative, several studies elucidating resistance mutations in DHFR from MRSA have been conducted in order to design new inhibitors and include the following: (1) evaluation of propargyl-linked inhibitors for TMP-resistant DHFR enzymes, (2) structural elucidation of TMP-resistant DHFR enzymes, (3) prospective prediction of resistance mutations in DHFR from MRSA using computational methods, and (4) determination of resistance profiles by selection with lead inhibitors in a MRSA strain. Concurrently, the conclusions from all of these studies will assist in the development of efficacious inhibitors for resistant strains of MRSA. ^