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Overcoming intrinsic resistance in gram-negative bacteria using small molecule adjuvants.

ABSTRACT: Gram-negative bacteria are intrinsically resistant to many classes of antibiotics, predominantly due to the impermeability of the outer membrane and the presence of efflux pumps. Small molecule adjuvants that circumvent these resistance mechanisms have the potential to expand therapeutic options for treating Gram-negative infections to encompass antibiotic classes that are otherwise limited to treating Gram-positive infections. Adjuvants that effect increased antibiotic permeation, either by physical disruption of the outer membrane or through interference with synthesis, transport, or assembly of membrane components, and adjuvants that limit efflux, are discussed as potential avenues to overcoming intrinsic resistance in Gram-negative bacteria.

SUBMITTER: Melander RJ

PROVIDER: S-EPMC9885958 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Overcoming intrinsic resistance in gram-negative bacteria using small molecule adjuvants.

Melander Roberta J RJ Mattingly Anne E AE Nemeth Ansley M AM Melander Christian C

Bioorganic & medicinal chemistry letters 20221223

Gram-negative bacteria are intrinsically resistant to many classes of antibiotics, predominantly due to the impermeability of the outer membrane and the presence of efflux pumps. Small molecule adjuvants that circumvent these resistance mechanisms have the potential to expand therapeutic options for treating Gram-negative infections to encompass antibiotic classes that are otherwise limited to treating Gram-positive infections. Adjuvants that effect increased antibiotic permeation, either by phy ...[more]

PMID: 36566797

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Project description:Gram-negative bacterial infections pose a significant challenge due to two major resistance elements, including the impermeability of the outer membrane and the overexpression of efflux pumps, which contribute to antibiotic resistance. Additionally, the coexistence of multispecies superbugs in mixed species biofilms further complicates treatment, as these infections are refractory to most antibiotics. To address this issue, combining obsolete antibiotics with non-antibiotic adjuvants that target bacterial membranes has shown promise in combating antibacterial resistance. However, the clinical translation of this cocktail therapy has been hindered by the toxicity associated with these membrane active adjuvants, mainly due to a limited understanding of their structure and mechanism of action. Towards this goal, herein, we have designed a small molecular adjuvant by tuning different structural parameters, such as the balance between hydrophilic and hydrophobic groups, spatial positioning of hydrophobicity and hydrogen bonding interactions, causing moderate membrane perturbation in bacterial cells without any toxicity to mammalian cells. Moderate membrane perturbation not only enhances the internalization of antibiotics, but also increases the intracellular concentration of drugs by hampering the efflux machinery. This revitalises the efficacy of various classes of antibiotics by 32-512 fold, without inducing toxicity. The leading combination not only exhibits potent bactericidal activity against A. baumannii biofilms but also effectively disrupts mature multispecies biofilms composed of A. baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which is typically resistant to most antibiotics. Importantly, the combination therapy demonstrates good biocompatibility and excellent in vivo antibacterial efficacy (>99% reduction) in a skin infection model of A. baumannii. Interestingly, A. baumannii shows reduced susceptibility to develop resistance against the leading combination, underscoring its potential for treating multi-drug resistant infections.

Dataset Information

Overcoming intrinsic resistance in gram-negative bacteria using small molecule adjuvants.

Publications

Overcoming intrinsic resistance in gram-negative bacteria using small molecule adjuvants.

Similar Datasets

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