Antimicrobial Resistance

Mechanisms of Resistance

Mechanisms of antimicrobial resistance can be broadly classified into four categories (Fig. 1):

• Enzymatic drug inactivation
• Modification of the antimicrobial target site
• Utilization of alternative metabolic pathways
• Reduced intracellular drug accumulation

These resistance strategies are not exclusive to antibacterial agents; they also underpin resistance to antifungal and antiviral therapies. The resistance mechanisms associated with commonly used antimicrobial agents are summarised in Table 1.

Enzymatic Modification/Inactivation

Some bacteria can produce enzymes that inactivate or chemically modify antimicrobial agents. For instance, staphylococci produce β-lactamases, which hydrolyse β-lactam antibiotics, thereby rendering them ineffective.

Alteration of Target Sites

• Resistance to β-lactam antibiotics through mutations in penicillin-binding proteins (PBPs), mediated by the mecA gene, is a well-established mechanism in methicillin-resistant Staphylococcus aureus (MRSA).
• In other bacteria, resistance may arise from the production of altered target enzymes with reduced susceptibility to antibiotic inhibition. For example, mutations in dihydrofolate reductase in trimethoprim-resistant bacteria markedly decrease the enzyme’s affinity for trimethoprim.

Alternative Metabolic Pathways

• Some bacteria develop alternative metabolic pathways that bypass the biochemical reactions inhibited by antibiotics. For example, certain sulphonamide-resistant bacteria can utilize preformed folic acid rather than relying on extracellular para-aminobenzoic acid (PABA).

Prevention of Drug Accumulation

• Reduced intracellular drug accumulation may result from decreased drug influx or increased drug efflux.
• Biofilm formation can further limit antimicrobial penetration and is commonly associated with difficult-to-treat soft tissue and pulmonary infections.
• Increased efflux occurs through the expression of membrane-associated channels or efflux pumps that actively transport antimicrobial agents out of the cell. This represents a major resistance mechanism in many Gram-negative bacteria, particularly against tetracyclines.
• Pseudomonas aeruginosa can form biofilms and expressing multidrug efflux pumps that expel a wide range of antimicrobial agents, contributing to its notable treatment challenges.

Created in BioRender. Boucher, M. (2026) https://BioRender.com/dezf6p5

Figure 1- Mechanisms of antibiotic resistance

Genetics of Antimicrobial Resistance

• Microbial resistance to antimicrobial agents may be intrinsic, reflecting an innate insensitivity to certain drugs, or acquired. Acquired resistance primarily arises through mutations in endogenous cellular genes or through the acquisition of exogenous DNA carried by mobile genetic elements (MGEs).

Chromosomal Resistance

• Spontaneous mutations occur at a low frequency, approximately one in 10⁶ to 10⁸ microorganisms, and therefore represent an uncommon source of antimicrobial resistance.
• Rifampicin is a notable exception, as resistance-conferring chromosomal mutations arise more frequently; a single point mutation in the rpoB gene, which encodes the rifampicin-binding site, can result in high-level resistance to rifampicin.
• Chromosomal mutants most commonly confer resistance through modification of the antimicrobial target site.

Extrachromosomal Resistance

Horizontal Gene Transfer

• Many antibiotic resistance genes are located on mobile genetic elements (MGEs), including plasmids and transposons, and can be transmitted between bacteria via horizontal gene transfer mechanisms such as transduction (transfer of bacteriophage-mediated DNA), conjugation (direct cell-to-cell DNA transfer through cytoplasmic connections), and transformation (uptake of free DNA fragments released from donor bacteria).
• Enzymatic inactivation of antibiotics is a predominant resistance mechanism associated with horizontally acquired genes, exemplified by the production of β-lactamases that hydrolyse penicillins and cephalosporins.

Vertical Gene Transfer

• This process occurs primarily through clonal expansion, whereby a single ancestral bacterium carrying resistance genes undergoes replication. Consequently, successive generations inherit these resistance determinants and are preferentially selected in environments where the corresponding antimicrobial agent is present.
• Notable contemporary examples include methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae.

Strategies to Overcome Antimicrobial Resistance

While it is hardly possible to eradicate antimicrobial resistance, a more thorough understanding of the mechanisms of antimicrobial resistance and their genetic origins would better allow health authorities to develop strategies to contain antimicrobial resistance.
Effort has been made to coordinate strategic approaches at both national and international levels. The UK Government has introduced a new five-year national action plan on antimicrobial resistance, titled Confronting antimicrobial resistance 2024–2029, which builds upon the successes and lessons learned from the initial national action plan

The aims of this plan include:

• optimise the use of antimicrobials
• reduce the need for, and unintentional exposure to, antibiotics
• support the development of new antimicrobials.

Optimising Antimicrobial Prescribing

Indiscriminate use of antibiotics is a major factor in growing antibiotic resistance and optimisation of antibiotic use through antimicrobial stewardship programmes is vitally important. Antimicrobial stewardship is defined as ‘an organisational or healthcare‑system‑wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness’.
The NHS 5 year AMR plan includes the following aims by 2029:

• Increase UK public and healthcare professionals’ knowledge on AMR by 10%, using 2018 and 2019 baselines, respectively
• Reduce total antibiotic use in human populations by 5% from the 2019 baseline

According to NICE guidance on antimicrobial stewardship, an AMS programme should be established in all care settings which could include the following:

• Monitoring and evaluation of antimicrobial prescribing, relating back to local resistance patterns
• Regular feedback to individual prescribers
• Education and training to healthcare providers
• Audit relating to AMS

Novel Drug Development

New drug class discovery has been disappointing, as the development of new drugs takes time (usually more than 10 years), and their relatively low return on investment compared to investments in other therapeutic areas acts as a deterrent.

WHO has identified a list of “priority pathogens” urgently requiring new antibiotics, including MRSA and Enterococcus faecium. Recently, a promising antimicrobial compound, Novltex, has been discovered, which has shown potent activity against both pathogens. Novltex has a different site of action, targeting lipid II, a building block of bacterial cell walls, which has not shown to mutate. This discovery shows future promise of a new target for antibiotics, however Novltex still requires clinical trials in humans to test safety and efficacy.

Table 1. Summary of resistance mechanisms of commonly used antimicrobial agents
*Resistance mechanisms of polyenes and echinocandins are speculative and being investigated.

References

1. Török ME, Cooke FJ, Moran E. Basics of antimicrobials. In: Oxford Handbook of Infectious Diseases and Microbiology. 2nd ed. Oxford: Oxford University Press; 2016.
2. Carroll K, Butel J, Morse S, Mietzner T. Jawetz, Melnick & Adelberg’s medical microbiology. 27th ed. New York: McGraw-Hill Education; 2016.
3. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 2015;13:42-51
4. Hoiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 2010;35:322-332.
5. Giedraitienė A, Vitkauskienė A, Naginienė R, Pavilonis A. Antibiotic resistance mechanisms of clinically important bacteria. Medicine (Kaunas) 2011;47(3):137-46.
6. Berger-Bächi B. Resistance Mechanisms of Gram Positive Bacteria. Int J Med Microbiol 2002;292:27-35.
7. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010; 74(3):417-433.
8. Meletis G, Exindari M, Vavatsi N, Sofianou D, Diza E. Mechanisms responsible for the emergence of carbapenem resistance in Pseudomonas aeruginosa. Hippokratia. 2012;16(4):303-307.
9. Doi Y, Arakawa Y. 16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides. Clin Infect Dis 2007;45:88-94.
10. Connell SR, Tracz DM, Nierhaus KH, Taylor DE. Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrob Agents Chemother 2003;47(12):3675-3681
11. Leclercq R. Mechanisms of resistance to macrolides and lincosamides: Nature of the resistance elements and their clinical implications. Clin Infect Dis 2002;34(4):482-492.
12. Department of Health. Confronting antimicrobial resistance 2024 to 2029 Accessed on 4/2/26. Available online: Confronting antimicrobial resistance 2024 to 2029 – GOV.UK
13. Malkawi, E. et al. (2025) ‘Novltex: A new class of antibiotics with potent activity against multidrug-resistant bacterial pathogens─design, synthesis, and biological evaluation’, Journal of Medicinal Chemistry, 68(18), pp. 19143–19152. doi:10.1021/acs.jmedchem.5c01193.
14. NICE (2015) Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use. Available at: https://www.nice.org.uk/guidance/ng15/chapter/Recommendations (Accessed: 04 February 2026).