The Challenge of Overcoming Antibiotic Resistance: An Adjuvant Approach?

Abstract

Antibiotic resistance is one of the greatest current threats to human health, and without significant action we face the chilling prospect of a world without effective antibiotics. Although continued effort toward the development of new antibiotics, particularly those with novel mechanisms of action, remains crucial, this alone probably will not be enough to prevail, and it is imperative that additional approaches are also explored. One such approach is the identification of adjuvants that augment the activity of current antibiotics. This approach has the potential to render an antibiotic against which bacteria have developed resistance once again effective, to broaden the spectrum of an antibiotic, and to lower the required dose of an antibiotic. In this viewpoint we discuss some of the advantages and disadvantages of the use of adjuvants, and describe various approaches to their identification.

Figure 1

Examples of adjuvant mechanisms of action and discovery: (A) inhibition of antibiotic modification; (B) inhibition of target modification; (C) inhibition of efflux; (D) enhancement of antibiotic uptake; (E) inhibition of signaling pathways that mediate antibiotic resistance; (F) inhibition of biofilm formation, which leads to increased antibiotic tolerance; (G) target-blind whole cell screening of previously approved drugs for adjuvant activity.

Figure 2

Examples of compounds that enhance antibiotic activity: (A) FDA-approved serine β-lactamase inhibitor clavulanic acid; (B) MBL inhibitor aspergillomarasmine A (AMA) restores meropenem activity against several Gram-negative species; (C) AME inhibitor exhibits synergism with kanamycin A against E. faecium; (D) efflux pump inhibitor Phe-Arg-β-naphthylamide (PAβN) increases the susceptibility of P. aeruginosa to levofloxacin; (E) pentamidine perturbs the Gram-negative membrane and sensitizes the bacteria to antibiotics whose activity is ordinarily limited to Gram-positive bacteria; (F) inhibitor of BlaR1 phosphorylation in MRSA increases susceptibility to β-lactam antibiotics; (G) 2-aminoimidazole derivative interferes with TCS signaling in A. baumannii to suppress colistin resistance; (H) quorum sensing inhibitor Hamamelitannin increases the sensitivity of S. aureus biofilms to several classes of antibiotics; (I) previously approved opioid-receptor agonist loperamide potentiates the effects of tetracycline antibiotics against several Gram-negative bacteria.