Author: Muñoz, Kristen A ; Wen, Po-Chao ; Ulrich, Rebecca J ; Lee, Hyang Yeon ; Lau, Gee W ; Hung, Chien-Che ; Holmes, Jessica R ; Sinclair, Matt ; Hergenrother, Paul J ; Tajkhorshid, Emad ; Vasan, Archit K ; Fields, Christopher J

Infections caused by Gram-negative pathogens are increasingly prevalent and are typically treated with broad-spectrum antibiotics, resulting in disruption of the gut microbiome and susceptibility to secondary infections^1-3. There is a critical need for antibiotics that are selective both for Gram-negative bacteria over Gram-positive bacteria, as well as for pathogenic bacteria over commensal bacteria. Here we report the design and discovery of lolamicin, a Gram-negative-specific antibiotic targeting the lipoprotein transport system. Lolamicin has activity against a panel of more than 130 multidrug-resistant clinical isolates, shows efficacy in multiple mouse models of acute pneumonia and septicaemia infection, and spares the gut microbiome in mice, preventing secondary infection with Clostridioides difficile. The selective killing of pathogenic Gram-negative bacteria by lolamicin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals; this doubly selective strategy can be a blueprint for the development of other microbiome-sparing antibiotics.

Infection

'Smart', microbiome-sparing antibacterial therapy with a focus on the novel Lolamicin: an overview

Review

Author: Ates, Furkan ; Rezaei, Ahmad Reza ; Sulik, Artur ; Toczyłowski, Kacper

PURPOSEAntibiotic resistance (AR) is an escalating worldwide health emergency, requiring inventive strategies for antibiotic treatment. This review examines the tactics used in designing smart antibiotics, with a specific emphasis on the mechanism of action of lolamicin, a newly developed microbiome-sparing antibiotic.METHODSWe review the recent advances in smart antibiotic development, particularly those aiming to preserve the gut microbiome while effectively targeting pathogens. The study focuses on lolamicin's selective targeting mechanism, its inhibition of the LolCDE complex in Gram-negative bacteria.RESULTSLolamicin works by blocking the LolCDE complex, which is crucial for transporting lipoproteins in Gramnegative bacteria. It offers a significant improvement compared to conventional antibiotics and other microbiomesparing options by safeguarding the microbiome and reducing the development of resistance. However, its limited range of effectiveness - namely against certain harmful bacteria such as Pseudomonas aeruginosa - and the possibility of bacteria becoming resistant to it, remain areas of concern.CONCLUSIONLolamicin presents a hopeful resolution by selectively attacking Gram-negative bacteria while leaving the beneficial gut flora unharmed. Further investigation and rigorous clinical testing are essential to fully harness its promise and confirm its long-term utility in combating antibiotic resistance.

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Negative Bacterial Infections	Preclinical	United States	University of Illinois At UrbanaChampaign	30 May 2024

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