Antimicrobial resistance is largely due to the overuse of antibiotics in humans, animals, and plants, with nearly all regions throughout the world affected by antibiotic-resistant diseases. Current estimates indicate that antimicrobial resistance is responsible for about 1.27 million deaths worldwide, with over 2.8 million individuals in the United States diagnosed with antimicrobial-resistant infections every year.1
The widespread prevalence of antimicrobial-resistant pathogens requires a thorough understanding of the different molecular mechanisms involved in the evolution of these species. These data are crucial for researchers to recognize global patterns of resistance and identify targets that can be used to design novel antibiotics that are less susceptible to resistance development.
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Role of Biotechnology in the Fight Against Antibiotic Resistance
Genetic Basis of Antibiotic Resistance
Bacteria are naturally equipped with the ability to adapt to a wide range of environmental challenges to survive and compete with other microorganisms in the environment.
This genetic flexibility, which is largely due to mobile genetic elements within the bacteria genome, has allowed bacteria to evolve and, combined with the selection pressure that arises due to extensive and, often, inappropriate antibiotic use, proliferate in the environment.
Acquired antibiotic resistance refers to genetic alterations that allow bacteria to become resistant to antibiotics that they were previously sensitive to. Although spontaneous mutations in chromosomal genes can lead to acquired resistance, horizontal gene transfer (HGT) is more commonly utilized by bacteria to gain resistant genes.3
Within the bacteria genome, several DNA elements, including plasmids, transposons, integrons, and chromosomal gene cassettes, are considered ‘mobile’ as they can move throughout the genome. During HGT, these genes are transferred to different organisms through conjugation, transduction, or transformation.
During conjugation, a sex pilus from the donor bacteria cell attaches to the recipient cell, thereby allowing genetic material to be transferred between the cells through the newly formed mating bridge. Transduction relies on bacteriophages, a type of virus that infects bacteria and archaea, to transfer genetic information, whereas transformation occurs after.
What causes antibiotic resistance? - Kevin Wu
Biochemical Mechanisms of Resistance
Alterations in enzymatic activity can also contribute to the development of antimicrobial resistance that leads to increased degradation or modification of the antibiotic molecule. For example, β-lactamases can hydrolyze the amide bond of the β-lactam ring, which ultimately leads to degradation of this drug class.
Novel carbapenemase enzymes are also continually being discovered, some of which include KPC-55, which can catalyze aztreonam and meropenem, as well as NDM-19, which can hydrolyze β-lactams, regardless of environmental zinc levels. Tetracycline-inactivating enzymes, the most notable of which include the Tet(X) family, have been identified in several classes of bacteria and can oxidize tetracyclines, thereby leading to their inactivation.2
Bacteria can also become resistant to antibiotics by modifying these molecules through the transfer of a chemical group. Acetyltransferases are capable of modifying the hydroxyl or amino groups of aminoglycosides, as well as transferring an acetyl group from coenzyme A to deactivate both phenicol and streptogramin antibiotics. Nucleotidyltransferases exhibit similar enzymatic activity for the modification of aminoglycosides, in addition to their addition of a phosphate-containing group to lincosamide antibiotics to render them ineffective.2
Antibiotics can also be transported from the cytoplasm to the extracellular fluid through a process known as active efflux, which relies on the activity of tripartite efflux pumps. In addition to antibiotics, bacteria also use their efflux pumps to transport toxic compounds, virulence factors, dyes, and detergents to their external environment.
By reducing the intracellular concentration of antibiotics, efflux pumps reduce the intracellular concentration of antibiotics, thereby reducing their antimicrobial efficacy.
Efflux pumps can be both natural and acquired, the latter of which are obtained by bacteria through HGT. Major facilitator superfamily (MFS) is a class of efflux pumps that is most commonly present in bacteria and humans and has been shown to confer resistance of Staphylococcus aureus to norfloxacin, biocides, and some dyes.3
Bacteria species can combine molecular mechanisms to become resistant to several classes of antibiotics, which subsequently leads to the emergence of multi-drug resistant strains such as vancomycin-resistant S. aureus (VRSA) and methicillin-resistant S. aureus (MRSA).
The Role of CRISPR in Developing Next-Generation Antibiotics
Future Directions in Antibiotic Resistance Research
The significant and growing threat that antibiotic resistance poses to public health and healthcare infrastructure worldwide emphasizes the crucial need to develop novel approaches to solving this issue. Recent advancements in artificial intelligence (AI) indicate the potential of this technology to revolutionize antibiotic discovery and development.
For example, machine learning (ML) and deep learning (DL) algorithms can analyze extensive data sets to identify previously unknown drug targets and resistant markers, as well as predict the efficacy of potential candidate molecules with desirable pharmacological properties.4
The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas 9 system is an extremely powerful and efficient genome editing technique that has also been investigated for its potential to reverse antimicrobial resistance.
These applications include correcting gene mutations in drug discovery processes and using CRISPR to investigate the role of new gene targets in antibiotic resistance.
Mining Bacteria for Next-Generation Antibiotics
Conclusions
Antimicrobial resistance is a multi-faceted issue that requires global coordination of human, animal, plant, and environmental policies to ensure our preparation for a potential antimicrobial crisis in the future.
Antibiotic stewardship programs, which combine expertise from a multidisciplinary team of infectious disease clinicians, pharmacists, microbiologists, hospital epidemiologists, and infection preventionists, have also been implemented to varying degrees in nations throughout the world to foster international collaboration in the fight against antibiotic resistance.
References
- “Antimicrobial resistance” [Online]. Available from: https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance.
- Darby, E. M., Trampari, E., Siasat, P., et al. (2022). Molecular mechanisms of antibiotic resistance revisited. Nature Reviews Microbiology 21; 280-295. doi:10.1038/s41579-024-01014-4.
- Brdova, D., Ruml, T., & Viktorova, J. (2024). Mechanism of staphylococcal resistance to clinically relevant antibiotics. Drug Resistance Updates 77. doi:10.1016/j.drup.2024.101147.
- Branda, F., & Scarpa, F. (2024). Implications of Artificial Intelligence in Addressing Antimicrobial Resistance: Innovations, Global Challenges, and Healthcare’s Future. Antibiotics 13(6). doi:10.3390/antibiotics13060502.
- Jaed, M. U., Hayat, M. T., Mukhtar, H., & Imre, K. (2023). CRISPR-Cas9 System: A Prospective Pathway toward Combatting Antibiotic Resistance. Antibiotics 12(6). doi:10.3390/antibiotics12061075.
Further Reading