Development of LolCDE inhibitors as microbiome-sparing gram-negative-selective antibiotics

Infections caused by gram-negative pathogens are on the rise and alarmingly, no new classes of antibiotics that target gram-negative bacteria have been approved by the Food and Drug Administration since the 1960s. Especially absent in our current antibiotic arsenal are gram-negative-only agents, with colistin being a notable exception that is exclusively used as a last resort for problematic gram-negative infections. Consequentially, gram-negative infections are typically treated with broad-spectrum antibiotics, resulting in damage to the gut microbiome and susceptibility to secondary diseases and infections. As such, there is a critical need for antibiotics that are selective for gram-negative bacteria over gram-positive bacteria, but also selective for pathogenic bacteria over commensal bacteria. Herein we report the development of a doubly selective strategy to design and discover lolamycin, a gram-negative-only antibiotic that targets the LolCDE lipoprotein transport system. Lolamycin has impressive activity against a panel of 125 multidrug-resistant clinical isolates, shows efficacy in multiple murine infection models whether dosed intraperitoneally or orally, spares the gut microbiome, and prevents secondary Clostridioides difficile infection. The selective killing of pathogenic gram-negative bacteria by lolamycin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals. With applications towards other bacterial proteins including BamA, LptD, or MsbA, this doubly selective strategy can serve as a blueprint for the development of microbiome-sparing antibiotics.

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

2023

Author dc:creator

• Munoz, Kristen Adriane

Contributors dc:contributor

• Hergenrother, Paul J
• Van Der Donk, Wilfred A
• Metcalf, William W
• Chan, Jefferson K

• Gram-negative Bacteria
• Gram-negative Antibiotics
• Gut Microbiome
• Narrow-spectrum
• Microbiome-sparing

Statement dc:rights

• Copyright 2023 Kristen Munoz

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/121186

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F121186