Mechanisms of Antibiotic Resistance

Antibiotic resistance is the heritable ability of bacteria to grow in the presence of a drug concentration that would normally inhibit them. Despite the diversity of antibacterial drugs, bacteria defeat them through a small repertoire of biochemical strategies — inactivating the drug, modifying or protecting its target, keeping the drug out, or pumping it back out — that can be encoded on the chromosome or acquired from other bacteria.

Definition

Antibiotic resistance is the capacity of a bacterial population to survive and replicate at drug concentrations that inhibit susceptible strains, achieved through enzymatic drug inactivation, target alteration or protection, reduced permeability, or active efflux, encoded by mutation or by acquired genes.

Scope

The entry organises resistance into its core biochemical mechanisms and its genetic basis, distinguishing intrinsic from acquired resistance and explaining how horizontal gene transfer disseminates resistance determinants. It is a reference and educational topic on how resistance works; it does not address the management of resistant infections.

Core questions

• What are the four principal biochemical mechanisms of resistance?
• How does intrinsic resistance differ from acquired resistance?
• How do mobile genetic elements spread resistance genes between bacteria?
• Why does multidrug resistance accumulate in some bacterial populations?

Key concepts

• Enzymatic drug inactivation (e.g. beta-lactamases, aminoglycoside-modifying enzymes)
• Target modification and target protection
• Reduced permeability (porin loss)
• Active efflux pumps
• Intrinsic versus acquired resistance
• Horizontal gene transfer (plasmids, transposons, integrons)
• Selection pressure and multidrug resistance

Mechanisms

Resistance operates through four recurring strategies. First, enzymatic inactivation, in which bacteria produce enzymes that chemically alter or destroy the drug — beta-lactamases hydrolysing the beta-lactam ring being the archetype (Bush & Bradford, 2016). Second, target modification or protection, where mutation, enzymatic modification of the target (such as ribosomal RNA methylation), or a protective protein lowers drug binding. Third, reduced uptake, often through loss or alteration of outer-membrane porins. Fourth, active efflux, in which membrane pumps expel the drug, frequently with broad substrate range that produces multidrug resistance (Blair et al., 2015; Alekshun & Levy, 2007). Genetically, resistance is either intrinsic (an inherent property of a species) or acquired by chromosomal mutation or by horizontal gene transfer; plasmids, transposons, and integrons carry and shuffle resistance genes between strains and species, accelerating dissemination (Partridge et al., 2018).

Clinical relevance

The biochemical and genetic mechanisms of resistance explain why particular organisms test resistant to particular drugs and how resistance spreads through populations, which underlies surveillance, infection control, and stewardship. This entry describes those mechanisms for orientation and study and does not provide guidance on treating resistant infections.

Epidemiology

Bacterial antimicrobial resistance is a leading global cause of death, associated with an estimated 4.95 million deaths in 2019 and directly attributable to about 1.27 million (Murray et al., 2022). The mobility of resistance genes on plasmids, transposons, and integrons allows determinants to cross between species and to assemble into multidrug-resistant lineages (Partridge et al., 2018).

History

Resistance was recognised soon after the first antibacterials entered use, and beta-lactamase activity was described even before penicillin's widespread clinical deployment. Over the following decades the discovery of plasmid-borne resistance and of integrons and transposons reframed resistance as a transferable, ecologically mobile trait rather than a fixed property of individual strains (Alekshun & Levy, 2007; Partridge et al., 2018).

Key figures

• Stuart B. Levy
• Laura J. V. Piddock
• Julian Davies

Seminal works

• blair-2015
• alekshun-levy-2007
• partridge-2018

Frequently asked questions

What are the main mechanisms by which bacteria resist antibiotics?

Four recurring strategies: inactivating the drug with enzymes, modifying or protecting the drug's target, reducing the drug's entry into the cell, and pumping the drug out via efflux.

How does antibiotic resistance spread between bacteria?

Largely through horizontal gene transfer, in which resistance genes carried on mobile elements such as plasmids, transposons, and integrons move between bacteria, sometimes across different species.