Antibiotic resistance (AR) is one of the most pressing global health issues of today’s world, causing millions of people to suffer from bacterial infections for prolonged periods. This article elaborates on the primary molecular mechanisms of AR, including enzymatic drug inactivation, target modification, efflux pump activity, and reduced permeability. It also explores how spontaneous mutations, horizontal and vertical gene transfer, play a role in the evolution and spread of resistance among certain bacterial cultures. Gaining an understanding of the molecular and genetic components of AR is crucial for developing novel treatments and implementing broad initiatives to preserve the effectiveness of antibiotics and protect public health.
Introduction
Antibiotics have significantly revolutionized modern medicine, saving the lives of millions since the 1940s. However, their effectiveness has decreased significantly since superbugs, including infectious bacteria, viruses, fungi, and other microbes, began developing antimicrobial resistance (AMR). According to the World Health Organisation, it is estimated that bacterial AMR was directly responsible for 1.27 million global deaths and contributed to 4.95 million deaths in 2019. Antibiotics are utilized in various sectors, including agriculture, aquaculture, animal husbandry, and, most importantly, human health. These substances are used to treat bacterial infections in humans, animals, and crops, thereby preventing crop loss from bacterial diseases.
Antibiotic resistance is the ability of bacteria to survive, grow, and multiply despite the presence of antibiotics in a medium that would normally kill or inhibit the growth of particular bacteria. It is a small subset of AMR, which includes resistance not only in bacteria but also in viruses, fungi, and other parasites. Bacteria can acquire resistance through spontaneous genetic mutations or by obtaining resistance genes from other microorganisms via horizontal gene transfer, a process that involves mechanisms such as conjugation, transformation, or transduction.
Molecular mechanisms of antibiotics to combat bacteria
To ensure selective toxicity, antibiotics typically target vital bacterial functions that are either absent or significantly altered in human cells. Yet, not all antibiotics have the exact mechanism of action. Understanding these mechanisms is crucial, as each represents a potential target that bacteria can evolve to resist, giving rise to the various forms of antibiotic resistance observed in clinical and environmental settings. They are commonly classified into 3 main mechanisms according to antibiotics’ own chemical structure, specific bacterial process, or structure they target as follows:
- Inhibition of cell wall synthesis
In this type of inhibition, antibiotics target the cell walls of bacteria, which are essential for maintaining cell shape and protecting against osmotic stress, primarily consisting of peptidoglycan and, in some cases, an additional outer layer. Peptidoglycan consists of two sugar chains – N-acetylglucosamine and N-acetylmuramic acid – connected by short peptide chains. Antibiotics, specifically β-lactams, bind to the transpeptidase enzyme, commonly known as penicillin-binding protein, and inhibit the formation of peptide bonds between sugar chains, thereby causing disruption of the cell wall.
- Inhibition of DNA replication
Bacterial cells use binary fission as a type of cell division to produce two daughter cells. Before cytokinesis, bacteria replicate their circular DNA using several enzymes, such as helicase for breaking down the hydrogen bonds between two strands, DNA gyrase for introducing negative supercoils ahead of the replication fork to relieve stress, and topoisomerase IV for separating two interlinked daughter chromosomes after replication is complete. Antibiotics, mostly fluoroquinolones (e.g., ciprofloxacin, levofloxacin), target DNA gyrase and topoisomerase IV, have a particular level of affinity to bind to the complex formed by DNA gyrase/topoisomerase IV and DNA itself. The enzyme-DNA complex is destabilized by such binding, resulting in DNA cleavage and, ultimately, bacterial cell death.
- Inhibition of protein synthesis
Unlike eukaryotic cells, bacteria synthesize proteins using 70S ribosomes, which consist of the 30S and 50S subunits. During translation, the 30S subunit decodes the mRNA sequence, while the 50S subunit catalyzes peptide bond formation between amino acids. Antibiotics like aminoglycosides (e.g., gentamicin, streptomycin), tetracyclines, and macrolides (e.g., erythromycin) act by binding to specific sites on the ribosomal subunits. For example, Tetracyclines prevent the attachment of aminoacyl-tRNA to the A site of the 30S subunit, halting elongation, while macrolides bind to the 23S rRNA of the 50S subunit, inhibiting peptidyl transferase activity and blocking peptide chain elongation. These antibiotics disrupt bacterial protein production by interfering with ribosome activity, in turn, negatively affecting cellular processes.
Bacterial strategies for antibiotic resistance
To survive under the selective pressures imposed by certain antibiotics, bacteria have developed various mechanisms to counteract their effects. The evolution of resistance is driven by genetic and phenotypic alterations that may occur spontaneously or be transferred among bacterial populations, facilitating the rapid spread of AR within bacterial culture. These adaptive strategies demonstrate how bacteria can modify their cellular and molecular behaviors to counteract or evade the effects of drugs:
- Enzymatic inactivation or modification of antibiotics
Bacteria can produce enzymes that chemically modify or inactivate antibiotics, preventing them from interacting with their intended targets. For example, β-lactamases hydrolyze the β-lactam ring in penicillins and cephalosporins, rendering these drugs ineffective against cell wall synthesis. Similarly, aminoglycoside-modifying enzymes, such as acetyltransferases, phosphotransferases, and nucleotidyltransferases, chemically alter aminoglycosides, preventing them from binding to the bacterial ribosome and terminating protein synthesis. These enzymatic modifications are highly specific to the antibiotic class and can be encoded on plasmids, allowing rapid dissemination among bacterial populations.
- Target modification
Another common resistance mechanism involves structural changes in the bacterial targets of antibiotics, thereby reducing the drug’s binding affinity. For instance, mutations in penicillin-binding proteins (PBPs) confer resistance to β-lactams by preventing the antibiotic from effectively inhibiting cell wall cross-linking. Similarly, alterations in ribosomal RNA or proteins can reduce binding of macrolides and aminoglycosides, while mutations in DNA gyrase or topoisomerase IV decrease susceptibility to fluoroquinolones. These modifications allow the bacterial enzyme or structure to maintain its essential function even in the presence of the antibiotic.
- Reduced permeability / Uptake inhibition
Bacteria can limit the entry of antibiotics by altering their outer membrane or porin proteins, especially in Gram-negative species. Changes in the size, number, or conformation of porins can reduce the uptake of hydrophilic antibiotics such as β-lactams and carbapenems, effectively lowering intracellular drug concentrations. This mechanism works synergistically with other resistance strategies, such as efflux pumps, to enhance survival in environments with high drug concentrations.
- Efflux pumps
Many bacteria possess transmembrane efflux systems that actively expel antibiotics from the cytoplasm before they reach their targets. For example, the AcrAB-TolC system in Escherichia coli and MexAB-OprM in Pseudomonas aeruginosa can remove multiple structurally unrelated antibiotics, contributing to multidrug resistance. Efflux pumps can be either constitutively expressed or inducible in response to antibiotic exposure, and their activity often correlates with reduced susceptibility to a wide range of drugs.
Global Threats to Public Health
Antibiotic resistance has emerged as one of the most critical global health threats of the 21st century. According to The Lancet’s 2024 global burden analysis, antimicrobial resistance continues to rise across every region and bacterial species studied (Murray et al., 2024). If current trends continue, the annual death toll is projected to exceed 10 million by 2050, surpassing those caused by cancer (WHO, 2023). This crisis is not confined to hospitals; resistant strains now circulate in communities, animals, and natural ecosystems, reflecting the interconnected “One Health” nature of AMR. The widespread use of antibiotics in agriculture and animal husbandry further accelerates the evolution and transmission of resistance. Beyond mortality, AMR threatens the success of modern medicine, making routine surgeries, childbirth, and cancer chemotherapy increasingly risky due to the loss of effective prophylactic antibiotics. Economically, the World Bank warns that by 2050, antibiotic resistance could cause a global GDP loss of up to 3.8%, pushing millions into extreme poverty. These findings underscore the importance of coordinated international strategies that combine surveillance, antimicrobial stewardship, research innovation, and public awareness to prevent a post-antibiotic era.
Final thought
Antibiotic resistance poses not only a scientific challenge but also a significant test of global responsibility. As germs continue to change faster than our ability to generate new treatments, the possibility of a post-antibiotic world becomes increasingly serious. Yet, this disaster is not irreversible. By combining molecular understanding with responsible policies, worldwide collaboration, and new research, we can preserve the effectiveness of antibiotics for future generations. Tackling AMR involves more than new medicines – it demands awareness, stewardship, and a widespread commitment to act before everyday infections once again become untreatable.
References
- Molecular mechanisms of antibiotic resistance (https://www.ars.usda.gov/alternativestoantibiotics/PDF/publications/MolMechAntibiotResistNRM2014.pdf)
- Biology of antimicrobial resistance and approaches to combat it (https://www.science.org/doi/full/10.1126/scitranslmed.aaz6992)
- Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050 (https://pubmed.ncbi.nlm.nih.gov/39299261/)
- Antibiotic action and resistance: updated review of mechanisms, spread, influencing factors, and alternative approaches for combating resistance (https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1305294/full)
- Antibiotic Resistance: What Is It, Complications & Treatment (https://my.clevelandclinic.org/health/articles/21655-antibiotic-resistance)
