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.

Figure 1

Mechanisms of resistance towards antibiotics. Created using BioRender.com.

Figure 2

Mechanisms by which different types of adjuvants can potentiate antibiotics. Created using BioRender.com.

Figure 3

Identifying potent antibiotic adjuvants. (A) Chequerboards to assess potentiating ability for potential antibiotic adjuvants. (B) Isobologram to assess synergistic, additive, or antagonistic interactions between two compounds. (C) Parameters for assessing antibiotic adjuvants. (B) is partially created using BioRender.com.

Figure 4

β-lactamase inhibitors (17–21) and inhibitors of aminoglycoside-inactivating enzymes (22–25).

Figure 5

Direct-acting efflux pump inhibitors.

Figure 6

Teichoic acid biosynthesis inhibitors/interactors.

Figure 7

Adjuvants targeting other cellular processes of bacteria.

Figure 8

Membrane-targeting polymyxin-derived and other peptides.

Figure 9

Small and macromolecular membrane-perturbing adjuvants.

Figure 10

Examples of indispensable SAR and preclinical studies undertaken for membrane-targeting compounds. (A) Correlation of the extent of membrane perturbation in norspermidine derivatives with varying structural moieties. (B) Correlation of activity and toxicity with varying structural moieties present in norspermidine derivatives. (C) Correlation of potentiation ability with the structure of norspermidine derivatives. (D) Scatter plot of compound synergy (FICI) with novobiocin against A. baumannii and lipophilicity (c log P) for pentamidine analogues. (E) Scatter plot of FICI and cytotoxicity for pentamidine analogues. (F) Pharmacokinetic analysis of the two best pentamidine analogues. (G) Microelectrode array (MEA) traces after exposure to different treatments to assess the beat period and field potential duration due to hERG trafficking inhibition. Figures adapted with permission from refs (199) (A to C) and (185) (D to G) from ACS Publications. Copyright ACS Publications 2022.

Figure 11

Adjuvants which modulate host response.

Figure 12

Directions to be explored for indirect resistance breakers, especially membrane-targeting adjuvants. Activity against bacterial biofilms, metabolically repressed bacteria, immunomodulatory functions, quorum sensing inhibition, and activity against intracellular infections can be explored for antibiotic adjuvants. Created using BioRender.com.