Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance

Abstract

The problem of antibiotic resistance is on the rise, with multidrug-resistant strains emerging even to the last resort antibiotics. The drug discovery process is often stalled by stringent cut-offs required for effective drug design. In such a scenario, it is prudent to delve into the varying mechanisms of resistance to existing antibiotics and target them to improve antibiotic efficacy. Nonantibiotic compounds called antibiotic adjuvants which target bacterial resistance can be used in combination with obsolete drugs for an improved therapeutic regime. The field of “antibiotic adjuvants” has gained significant traction in recent years where mechanisms other than β-lactamase inhibition have been explored. This review discusses the multitude of acquired and inherent resistance mechanisms employed by bacteria to resist antibiotic action. The major focus of this review is how to target these resistance mechanisms by the use of antibiotic adjuvants. Different types of direct acting and indirect resistance breakers are discussed including enzyme inhibitors, efflux pump inhibitors, inhibitors of teichoic acid synthesis, and other cellular processes. The multifaceted class of membrane-targeting compounds with poly pharmacological effects and the potential of host immune-modulating compounds have also been reviewed. We conclude with providing insights about the existing challenges preventing clinical translation of different classes of adjuvants, especially membrane-perturbing compounds, and a framework about the possible directions which can be pursued to fill this gap. Antibiotic–adjuvant combinatorial therapy indeed has immense potential to be used as an upcoming orthogonal strategy to conventional antibiotic discovery.

Small molecular adjuvants repurpose antibiotics towards Gram-negative bacterial infections and multispecies bacterial biofilms

“…26,27 Recently, another three drugs approved for non-antimicrobial indications, namely 5-fluorouracil, fluspirilene, and Bay 11-7082, resensitized a clinical strain of A. baumannii to azithromycin. 28…”

Dual functional therapeutics: mitigating bacterial infection and associated inflammation

“…However, the increasing emergence of antimicrobial resistance is threatening to undo the gains of the last century. 1 Along with increasing antimicrobial resistance, infection associated conditions, such as hyperimmune response, cytokine storm, and sepsis, lead to many complications in therapy. The co-occurrence of bacterial infection and associated inflammation severely jeopardises public health.…”

“…However, the increasing emergence of antimicrobial resistance is threatening to undo the gains of the last century. 1 Along with increasing antimicrobial resistance, infection associated This journal is © The Royal Society of Chemistry 2023…”

Xanthone Derivatives Enhance the Therapeutic Potential of Neomycin against Polymicrobial Gram-Negative Bacterial Infections

“…Antibiotic adjuvants are clinically employed to enhance the therapeutic potential of existing antibiotics by inhibiting the corresponding degrading enzymes, inhibiting efflux pumps, and permeabilizing bacterial membranes. 13,14 Cationic amphiphilic molecules having different amino acid residues can target the bacterial membranes and can manage microbial infections. 15−19 In addition, the class of membrane-permeabilizers can also enhance the effectiveness of existing antibiotics against drug-resistant pathogens as well as clinical isolates.…”

“…Antibiotic adjuvants are clinically employed to enhance the therapeutic potential of existing antibiotics by inhibiting the corresponding degrading enzymes, inhibiting efflux pumps, and permeabilizing bacterial membranes. , Cationic amphiphilic molecules having different amino acid residues can target the bacterial membranes and can manage microbial infections. − In addition, the class of membrane-permeabilizers can also enhance the effectiveness of existing antibiotics against drug-resistant pathogens as well as clinical isolates . These molecules engage in electrostatic interactions with outer and inner bacterial membranes, resulting in their disruption that facilitates the penetration of antibiotics such as erythromycin in the bacterial cells. , However, poor selectivity of these membrane-permeabilizers for bacterial membranes and their toxicity against mammalian cells bring challenges for clinical translation .…”