4.5 Article

Small-Molecular Adjuvants with Weak Membrane Perturbation Potentiate Antibiotics against Gram-Negative Superbugs

Journal

ACS INFECTIOUS DISEASES
Volume 8, Issue 5, Pages 1086-1097

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.2c00092

Keywords

adjuvants; antibiotics; antimicrobial resistance; Gram-negative bacteria; membrane perturbation

Funding

  1. SERB, Govt. of India [CRG/2020/003118]
  2. DBT [BT/PR31801/MED/29/1394/2019]

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This article discusses the prospects and challenges of combination therapy with membrane-targeting compounds in the treatment of multidrug-resistant bacterial infections, as well as the structural influence on membrane perturbation, activity, and toxicity of antibiotic potentiators or adjuvants. By incorporating cyclic hydrophobic moieties, antibiotic adjuvants with weak membrane perturbation and negligible in vitro toxicity but good potentiating ability have been developed. Aryl or adamantane functionalized derivatives showed better potentiation, increasing the sensitivity of critical Gram-negative superbugs to multiple classes of antibiotics. The mechanism of potentiation involved weak outer-membrane permeabilization, membrane depolarization, and efflux inhibition. This concept of weakly perturbing the membrane through chemical design has the potential to revitalize the effectiveness of obsolete antibiotics for the treatment of complicated Gram-negative bacterial infections.
Combination therapy with membrane-targeting compounds is at the forefront because the bacterial membrane is an attractive target considering its role in various multidrug-resistant elements. However, this strategy is crippled by the toxicity associated with these agents. The structural requirements for optimum membrane perturbation and minimum toxicity have not been explored for membrane-targeting antibiotic potentiators or adjuvants. Here, we report the structural influence of different chemical moieties on membrane perturbation, activity, toxicity, and potentiating ability in norspermidine derivatives. It has been shown in this report that weak membrane perturbation, achieved by the incorporation of cyclic hydrophobic moieties, is an effective strategy to design antibiotic adjuvants with negligible in vitro toxicity and activity but good potentiating ability. Aryl or adamantane functionalized derivatives were found to be better resorts as opposed to the acyclic analogues, exhibiting as high as 4096-fold potentiation of multiple classes of antibiotics toward critical Gram-negative superbugs. The mechanism of potentiation was nonspecific, consisting of weak outer-membrane permeabilization, membrane depolarization, and efflux inhibition. This unique concept of weakly perturbing the membrane by incorporating cyclic hydrophobic moieties in a chemical design with free amine groups serves as a breakthrough for nontoxic membrane-perturbing adjuvants and has the potential to revitalize the effect of obsolete antibiotics to treat complicated Gram negative bacterial infections.

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