Biophysical Society Thematic Meeting

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

, Erick Strauss

Stellenbosch University, Stellenbosch, South Africa,

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

PanK-II. Furthermore, we used the

PanK-II

crystal structure (PDB 4M7X) to rationalize why some of the analogues acted as poor substrates

for

PanK-II and as poor inhibitors for

S. aureus.