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A broad-spectrum synthetic antibiotic that does not evoke bacterial resistance.
Heithoff, Douglas M; Mahan, Scott P; Barnes V, Lucien; Leyn, Semen A; George, Cyril X; Zlamal, Jaime E; Limwongyut, Jakkarin; Bazan, Guillermo C; Fried, Jeffrey C; Fitzgibbons, Lynn N; House, John K; Samuel, Charles E; Osterman, Andrei L; Low, David A; Mahan, Michael J.
Afiliación
  • Heithoff DM; 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.
  • Mahan SP; 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, Universi
  • Barnes V L; 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.
  • Leyn SA; Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • George CX; 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.
  • Zlamal JE; Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • Limwongyut J; 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.
  • Bazan GC; 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,
  • Fried JC; 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.
  • Fitzgibbons LN; 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.
  • House JK; Faculty of Science, Sydney School of Veterinary Science, The University of Sydney, Camden, New South Wales, 2570, Australia.
  • Samuel CE; 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.
  • Osterman AL; Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • Low DA; 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.
  • Mahan MJ; 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.
EBioMedicine ; 89: 104461, 2023 Mar.
Article en En | MEDLINE | ID: mdl-36801104
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Infecciones Bacterianas / Sepsis / Antiinfecciosos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: EBioMedicine Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Infecciones Bacterianas / Sepsis / Antiinfecciosos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: EBioMedicine Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos