A broad-spectrum synthetic antibiotic that does not evoke bacterial resistance

Douglas M Heithoff; Scott P Mahan; Lucien Barnes V; Semen A Leyn; Cyril X George; Jaime E Zlamal; Jakkarin Limwongyut; Guillermo C Bazan; Jeffrey C Fried; Lynn N Fitzgibbons; John K House; Charles E Samuel; Andrei L Osterman; David A Low; Michael J Mahan

doi:10.1016/j.ebiom.2023.104461

A broad-spectrum synthetic antibiotic that does not evoke bacterial resistance

EBioMedicine. 2023 Mar:89:104461. doi: 10.1016/j.ebiom.2023.104461. Epub 2023 Feb 15.

Authors

Affiliations

¹ Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA.
² Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, 95616, USA.
³ Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
⁴ Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA; Center for Polymers and Organic Solids, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
⁵ Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA; Center for Polymers and Organic Solids, Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA; Department of Chemistry, National University of Singapore, 117543, Singapore.
⁶ Department of Medical Education, Santa Barbara Cottage Hospital, Santa Barbara, CA, 93105, USA; Department of Pulmonary and Critical Care Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, 93105, USA.
⁷ Department of Medical Education, Santa Barbara Cottage Hospital, Santa Barbara, CA, 93105, USA; Division of Infectious Diseases, Santa Barbara Cottage Hospital, Santa Barbara, CA, 93105, USA.
⁸ Faculty of Science, Sydney School of Veterinary Science, The University of Sydney, Camden, New South Wales, 2570, Australia.
⁹ Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA. Electronic address: dlow@ucsb.edu.
¹⁰ Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA, 93106, USA. Electronic address: mahan@ucsb.edu.

Abstract

Background: Antimicrobial resistance (AMR) poses a critical threat to public health and disproportionately affects the health and well-being of persons in low-income and middle-income countries. Our aim was to identify synthetic antimicrobials termed conjugated oligoelectrolytes (COEs) that effectively treated AMR infections and whose structures could be readily modified to address current and anticipated patient needs.

Methods: Fifteen chemical variants were synthesized that contain specific alterations to the COE modular structure, and each variant was evaluated for broad-spectrum antibacterial activity and for in vitro cytotoxicity in cultured mammalian cells. Antibiotic efficacy was analyzed in murine models of sepsis; in vivo toxicity was evaluated via a blinded study of mouse clinical signs as an outcome of drug treatment.

Findings: We identified a compound, COE2-2hexyl, that displayed broad-spectrum antibacterial activity. This compound cured mice infected with clinical bacterial isolates derived from patients with refractory bacteremia and did not evoke bacterial resistance. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to negate bacterial cell viability and the evolution of drug-resistance. Disruption of these bacterial properties may occur through alteration of critical protein-protein or protein-lipid membrane interfaces-a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis.

Interpretation: The ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. These COE features enable the construction of a spectrum of compounds with the potential for development as a new versatile therapy for an imminent global health crisis.

Funding: U.S. Army Research Office, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute.

Keywords: Antibiotics; Antimicrobial resistance; COE; Conjugated oligoelectrolytes; Multidrug-resistant pathogens.

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Anti-Infective Agents* / pharmacology
Bacteria
Bacterial Infections* / microbiology
Drug Resistance, Multiple, Bacterial
Mammals
Mice
Microbial Sensitivity Tests
Sepsis* / drug therapy

Substances

Anti-Bacterial Agents
Anti-Infective Agents

Abstract

MeSH terms

Substances

Grants and funding