Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts

3-POS Board 3 Developing Degradation Resistant Antimicrobials Leanne Barnard 1,2 , Willem Van Otterlo 2 , Erick Strauss 1 . 1 Stellenbosch University, Stellenbosch, South Africa, 2 Stellenbosch University, Stellenbosch, South Africa. The emergence of multidrug-resistant organisms is one of the main driving forces for the continuous development of new antimicrobial chemotherapies. Previous research established that Coenzyme A (CoA) promotes the growth of various disease-causing bacteria, including Staphylococcus aureus , Plasmodium falciparum and Mycobacterium tuberculosis . Consequently, the CoA biosynthetic pathway is seen as a prospective target for antimicrobial chemotherapies. The first committed step in CoA biosynthesis entails the ATP-dependent phosphorylation of pantothenic acid (Vitamin B5) to 4’-phosphopantothenic acid by pantothenate kinase (PanK). Recent in vitro studies have provided evidence that PanK is inhibited by a class of pantothenic acid analogues, namely N-substituted pantothenamides. However, this promising antimicrobial activity is lost when such tests are performed in vivo due to enzymatic degradation of the pantothenamides by pantetheinase enzymes. This study focused on the design and synthesis of new potent inhibitors (based on the pantothenamide scaffold) that are resistant to degradation caused by the pantetheinase enzymes. This will be achieved by making modifications to current potent pantothenamide growth inhibitors to protect the amide bond from hydrolysis. Specifically, the amide bond will be modified to be more sterically hindered though the addition of methyl groups, or by replacing it with a bioisostere moiety that should withstand pantetheinase degradation. From ten proposed compounds, we successfully synthesized 9 derivatives to date which include bioisosteres such as sulfonamides, thioamides, hydrazides as well as methylations either on the α-carbon, β-carbon or the amide bond. These compounds we tested to determine whether they still act as potent inhibitors of S. aureus and Sa PanK-II. Furthermore, we used the Sa PanK-II crystal structure (PDB 4M7X) to rationalize why some of the analogues acted as poor substrates for Sa PanK-II and as poor inhibitors for S. aureus.

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