Antimicrobial resistance in healthcare, agriculture and the environment: the biochemistry behind the headlines

Abstract

The crisis of antimicrobial resistance (AMR) is one of the most serious issues facing us today. The scale of the problem is illustrated by the recent commitment of Heads of State at the UN to coordinate efforts to curb the spread of AMR infections. In this review, we explore the biochemistry behind the headlines of a few stories that were recently published in the public media. We focus on examples from three different issues related to AMR: (i) hospital-acquired infections, (ii) the spread of resistance through animals and/or the environment and (iii) the role of antimicrobial soaps and other products containing disinfectants in the dissemination of AMR. Although these stories stem from three very different settings, the underlying message in all of them is the same: there is a direct relationship between the use of antimicrobials and the development of resistance. In addition, one type of antimicrobial could select for cross-resistance to another type and/or for multidrug resistance. Therefore, we argue the case for increased stewardship to not only cover clinical use of antibiotics, but also the use of antimicrobials in agriculture and stewardship of our crucially important biocides such as chlorhexidine.

Keywords: antimicrobial resistance; antiseptic; cross-resistance; hospital acquired infections; last resort antibiotic; spread of resistance.

Figure 1. Timeline of selected antibiotic development and reported resistance

A mechanism of resistance is illustrated for each antibiotic. Penicillin is commonly inactivated by bacterial β-lactamases, which cleave the β-lactam ring, forming the inactive penicilloic acid. Subsequent development of methicillin utilized a larger aryl side chain that was largely resistant to hydrolytic cleavage by β-lactamases. Instead, resistance to methicillin is driven by the expression of the alternative transpeptidase, PBP2a, which has a lower affinity for methicillin and can catalyse peptidoglycan cross-linking despite methicillin intervention. Resistance to vancomycin is driven by structural alteration of the terminal dipeptide that is modified from d-alanyl-d-alanine (d-Ala-d-Ala) to d-alanyl-d-lactate (d-Ala-d-Lac), reducing the affinity of the dipeptide for vancomycin and preventing disruption of peptidoglycan cross-linking.

Figure 2. Selected mechanisms of colistin resistance

The bactericidal activity of colistin relies on disruption of the bacterial cell membrane, initiated by electrostatic interaction between colistin and the lipid A portion of bacterial LPS. Immediate, albeit non-specific, resistance to colistin is mediated through transcriptional up-regulation of drug efflux pumps. Specific resistance to colistin is facilitated by the plasmid-mediated mcr-1 gene, encoding a phosphoethanolamine transferase, which modifies lipid A with a phosphoethanolamine (PEP) group, preventing interaction between colistin and lipid A.

Figure 3. Biocide usage and antibiotic resistance

Biocides such as triclosan and chlorhexidine exert their antimicrobial activity through non-specific interactions with cellular targets. An innate bacterial defence to toxic compounds, such as these, is up-regulation of multidrug efflux pumps, such as qacA in the Gram-positive organism S. aureus and mexAB-oprM in the Gram-negative organism P. aeruginosa. Once expressed, these efflux pathways will not only export biocides, but also antibiotics, antiseptics, heavy metals and dyes – hence resulting in the development of multidrug resistance.