| |
| author |
Benjamin Strickland
| | title |
In Silico Discovery of FtsZ Inhibitors for the Treatment of Multidrug-Resistant Staphylococcus aureus
| | abstract |
Pathogenic bacteria resistant to current first-line antibiotic treatments in the
United States are responsible for two million infections a year, placing a strain upon the
United States healthcare system and increasing expenditure by an estimated $20 billion
per year in associated medical costs. Of particular concern is the pathogenic bacterium
methicillin-resistant Staphylococcus aureus (MRSA), which exhibits resistance towards
almost all clinical β-lactams (e.g. penicillins, cephalosporins, and carbapenems). MRSA
commonly acquires additional resistance determinants, giving rise to multidrug-resistant
MRSA subtypes (MDRSA) which can be especially challenging to treat. The bacterial
cellular division protein Filamenting temperature-sensitive mutant Z (FtsZ) represents a
novel and attractive target for combating such multidrug-resistant infections, with
efficacious preclinical allosteric FtsZ inhibitors of the benzamide family reported in
literature. However, benzamide-resistant MRSA FtsZ isolates (G193D, G196S, N263K)
hinder application of this compound class, with N263K-mutant FtsZ inducing steric
occlusion to the benzamide pharmacophore and conferring resistance to all presently
known members of the benzamide family. Accordingly, there is a compelling requisite
for the discovery of novel inhibitors of FtsZ which are unhindered by recognized FtsZ
structural mutations. Ten promising lead-like candidate FtsZ inhibitors were identified
through an evolutionary virtual high throughput screening. All proposed inhibitors
exhibit favorable predicted absorption, distribution, metabolism, excretion, and toxicity
properties suitable for a lead-like candidate, and predicted potencies surpass that of the
preclinical benzamide TXA707 against the clinically relevant S. aureus MRSA252 strain
and the G196S FtsZ mutant, the most common mutant conferring resistance to the
benzamide, TXA707. A three-member subset of the ten proposed candidate FtsZ
inhibitors (BGS-HT(F)_005, BGS-HT(F)_026, BGS-HT(F)_027), all contain a common
propionic acid functionality, and demonstrate robust binding modes unaffected by the
G196S and N263K mutations. Accordingly, BGS-HT(F)_005, BGS-HT(F)_026, and
BGS-HT(F)_027 may hold promise as novel lead-like inhibitors of FtsZ for the treatment
of resistant bacterial infections.
| | school |
The College of Liberal Arts, Drew University
| | degree |
B.A. (2021)
|
| advisor |
Vincent Gullo
|
| committee |
Adam Cassano
Joanna Miller
|
| full text | BStrickland.pdf - requires Drew uLogin |
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