Development of novel compounds to improve the resistance profile and spectrum of activity of fusidic acid

Recent reports indicate that antibiotic-resistant bacterial infections are rising and represent one of the most serious threats humans face today. Even more worrisome is the lack of treatment options to combat these pathogens as no new classes of antibiotics that target Gram-negative bacteria have been approved by the Food and Drug Administration (FDA) since the introduction of the fluoroquinolones in 1968. While seven new classes of Gram-positive-only antibiotics have been introduced to the market since 1968, the detection of bacteria that are resistant to vancomycin, a last resort Gram-positive-only antibiotic, highlights the severity of resistance towards Gram-positive antibiotics. The clear need for novel agents to target both Gram-positive and Gram-negative pathogens motivated us to investigate Fusidic Acid (FA), a Gram-positive-only antibiotic as a novel solution to combat these deadly pathogens. Herein, we report the development of FA-CP, the first analogue of FA with equipotent activity. FA-CP also shows an improvement in activity against FA-resistant strains relative to FA. The improvement in activity was then translated to an in vivo model, where FA-CP shows activity against an FA-resistant strain. Noteworthy is the fact that FA shows no efficacy against this strain and that the strain possesses a fusA mutation that has been observed in clinical isolates of FA. To enhance the activity of FA against Gram-negative pathogens, a novel platform was developed that generated the first FA derivative with whole cell activity against a variety of Gram-negative pathogens and clinical isolates of P. aeruginosa and E. coli. Excitingly, this novel conversion platform could be applied to other Gram-positive-only antibiotics to generate new broad-spectrum agents. Finally, we report that one of our synthesized FA derivatives, FA-Oxane, shows good activity against replicating and dormant Mycobacterium tuberculosis. FA-Oxane is three times better tolerated in vivo and shows a drastically improved pharmacokinetic profile relative to FA, which is exciting because the poor pharmacokinetic profile of FA has been detrimental to the advancement of FA as a clinical candidate. The drastic improvement in pharmacokinetic profile of FA-Oxane provides optimism that this compound could not only show efficacy in vivo against dormant tuberculosis, but could also be used to treat vancomycin-resistant Enterococcus (VRE) and Gram-negative pathogens such as Neisseria gonorrhoeae. The excellent cell culture selectivity, whole cell activity, in vivo tolerability, and pharmacokinetic profile offers enthusiasm that FA-Oxane has the properties to become a clinical candidate.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Chavez, Martin Garcia

Contributors dc:contributor

• Hergenrother, Paul J
• van der Donk, Wilfred A
• Mehta, Angad P
• Sarlah, David

• Fusidic Acid, Antibiotics

Statement dc:rights

• Copyright 2021 Martin Chavez

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/113266

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/113266