Antimicrobial resistance (AMR) poses a significant threat to public health worldwide. Overuse and misuse of antibiotics have led to the emergence and spread of resistant bacteria, rendering many common infections difficult or impossible to treat. In response to this urgent global challenge, researchers and healthcare professionals are exploring a wide range of strategies and innovations to combat AMR.
Fig. 1 Categories of alternative strategies to combat antimicrobial resistance (Murugaiyan J., et al. 2022).
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Conventional Antibiotic Therapy to Combination Therapy
Antibiotics are grouped based on their molecular class and primary mode of action, including targeting cell membranes, walls, protein, DNA, RNA, and metabolic compounds. Antibiotic resistance mechanisms are driven by various factors, leading to the development of resistance. Understanding these mechanisms has led to the development of resistance inhibitors. Antibiotic combination therapy involves using two or more antibiotics simultaneously to achieve synergistic effects. Various combinations have been studied, with some showing success in treating multidrug-resistant infections. For β-lactam antibiotic-resistant infections, combining β-lactam antibiotics with β-lactamase inhibitors can restore the antibiotics' effectiveness. Moreover, combining antibiotics with biocides has shown potential, but further research is needed to understand their effects. Overall, combination therapy offers a promising approach to combat antibiotic resistance and should be continuously evaluated to improve treatment efficacy.
Strategies Targeting Antimicrobial-Resistant Enzymes
Enzyme Inhibitors
Enzyme inhibitors are small synthetic molecules that can either partially or completely inhibit the catalytic activity of enzymes, either reversibly or irreversibly. Many antibiotics target enzymes, and bacterial enzymes are often involved in resistance development against these antibiotics. For instance, penicillin-binding proteins (PBPs) are crucial for bacterial cell wall synthesis and serve as targets for antibiotics like penicillin. Enzyme inhibitors like clavulanic acid, commonly used in combination with β-lactam antibiotics, can restore antibiotic efficacy by inactivating β-lactamases. Research is ongoing to evaluate other inhibitors as potential weapons against clinically relevant antibiotic-resistant pathogens.
Medicinal Plants and Phytochemicals
Plants produce a wide array of secondary metabolites known as phytochemicals, some of which possess potent antimicrobial properties. Alkaloids, organosulfur compounds, phenolic compounds, coumarins, and terpenes are among the phytochemicals showing promising antibacterial activity. These compounds can inhibit various bacterial functions, including cell wall synthesis, biofilm formation, and efflux pump activity. Their efficacy against multidrug-resistant (MDR) bacteria makes them potential candidates for developing novel antibiotics. Additionally, phytochemicals may serve as alternatives to antibiotic growth promoters in livestock farming.
Small Molecules-Improved Chemical Entities (ICE)
Advances in genomics and innovative technologies have enabled the exploration of small molecules as potential antibiotics. Antimicrobial peptides (AMPs) and enzyme inhibitors, such as LpxC inhibitors, are among the newer compounds being investigated. AMPs exhibit broad-spectrum activity but face challenges related to stability and toxicity. Inhibitors targeting essential enzymes, like LpxC, show promise in selectively targeting Gram-negative pathogens. However, more research is needed to overcome current limitations and revitalize the antibiotic pipeline.
Essential Oils
Essential oils (EOs) derived from plants contain volatile compounds with antimicrobial properties. These oils disrupt bacterial cell membranes and inhibit efflux pumps, among other mechanisms. EOs like cinnamon bark, lavender, peppermint, and tea tree oil have demonstrated antibacterial activity against MDR bacteria. Coupling EOs with nanoparticle technology could enhance their stability and solubility, offering potential applications in clinical practice and food preservation.
RNA Silencing
RNA silencing is a natural mechanism found in bacteria that regulates gene expression. Synthetic antisense sequences can be developed to target enzymes involved in antibiotic resistance. This strategy has been used in antibacterial screening to knock down target genes and identify novel antibiotics. RNA silencing offers insights into the mode of action of antimicrobial agents and holds potential for developing sequence-specific antimicrobials.
CRISPR-Cas System
The CRISPR-Cas system is a bacterial immune system that can target and eliminate foreign genetic material, including antibiotic resistance genes. CRISPR-Cas gene-editing tools show promise in selectively removing antimicrobial resistance genes and sensitizing bacteria to antibiotics. Further research is needed to address delivery issues and potential off-target effects, but CRISPR-Cas systems offer new opportunities for combating antimicrobial resistance.
Strategies Targeting Antimicrobial-Resistant Bacteria
The battle against antimicrobial resistance (AMR) requires a multifaceted approach, and several innovative strategies have emerged to combat this global threat. Among these strategies, lantibiotics, bacteriocins, antimicrobial peptides (AMPs), insect-derived enzymes and AMPs, nanoparticle-based methods, coinfection strategies with probiotic bacteria, monoclonal antibodies (mAbs), bacteriophage therapy, biofilm dispersion techniques, anti-persister antimicrobials, and disruption of quorum sensing play pivotal roles.
Lantibiotics and Bacteriocins
Lantibiotics, gene-encoded peptides containing unusual amino acids like lanthionine and methyllanthionine, exhibit antimicrobial activity primarily against Gram-positive bacteria. They are classified into type-A and type-B peptides, each with distinct mechanisms of action. Bacteriocins, a type-A lantibiotic produced by bacteria, are proteinaceous toxins targeting closely related bacterial strains, presenting potential in treating various infections, including biofilms.
Antimicrobial Peptides (AMPs)
AMPs, ranging from 10 to 50 amino acids, possess a cationic charge and amphipathic nature, offering broad-spectrum antimicrobial activity. Synthetic peptides, designed based on natural AMPs, exhibit enhanced efficacy. Challenges like proteolytic degradation and toxicity necessitate innovative delivery methods like nanotechnology-based carriers and combination therapy with traditional antibiotics.
Insect-Derived Enzymes and AMPs
Insects produce diverse antimicrobial peptides categorized into four groups based on structure and composition. These peptides exhibit antibiofilm and antibacterial properties, potentially serving as novel therapeutics. Moreover, they demonstrate similarity to human immune molecules, offering promising avenues for research.
Nanoparticle-Based Strategies
Nanoparticles inhibit bacterial growth through various mechanisms, including oxidative stress and membrane disruption. Despite their efficacy, toxicity concerns necessitate targeted delivery methods to mitigate adverse effects.
Coinfection Strategies & Probiotic Bacteria
Probiotics, administered orally, confer health benefits by preventing infections through ecological mechanisms. While probiotics reduce antibiotic usage and selective pressure on pathogens, they pose risks of AMR transmission, necessitating rigorous safety assessment.
Monoclonal Antibodies (mAbs)
mAbs target surface antigens or toxins of bacteria, providing specificity and potential advantages over traditional antibiotics. Despite limited approvals, ongoing research explores their efficacy in treating bacterial infections.
Bacteriophages-Based Therapies
Phage therapy, harnessing bacteriophages to infect and replicate within bacteria, offers a promising avenue to combat AMR. Phage-derived lytic proteins exhibit bactericidal activity against a wide range of pathogens, presenting an eco-friendly approach for food safety and clinical applications.
Biofilm Dispersion Methods
Biofilms contribute to antibiotic resistance, and strategies targeting biofilm dispersion offer potential therapeutic options. Active and passive dispersion mechanisms aim to disrupt biofilm integrity, enhancing susceptibility to antimicrobial agents.
Anti-Persister Antimicrobials
Persistence, a bacterial survival mechanism, leads to chronic infections and AMR. Anti-persister drugs target persister cells, enhancing the eradication of resilient bacterial populations.
Disruption of Quorum Sensing
Quorum sensing regulates biofilm formation and virulence in bacteria. Strategies disrupting quorum sensing offer therapeutic potential by reducing bacterial pathogenicity and enhancing susceptibility to antimicrobials.
Strategies Based on Drug Delivery Systems
Drug delivery systems offer strategic avenues to address challenges in antibiotic research. A key hurdle is antibiotics' limited cell permeability. Antimicrobial delivery systems hold promise in enhancing antibiotic penetration into bacterial cells. Leveraging bacterial iron transport systems is pivotal. Synthetic siderophores, when coupled with antibiotics, facilitate their entry into bacteria. For instance, conjugating ampicillin with synthetic siderophores resulted in significantly increased activity against P. aeruginosa and gram-negative enterobacteria, bypassing efflux pump resistance mechanisms. Polymeric nanoparticles are emerging as another solution, enhancing antimicrobial solubility, stability, and bioavailability while reducing microbiota exposure to sub-lethal doses. These nanoparticles enable precise drug release and are synthesized from biocompatible materials like chitosan, collagen, or polyethylene glycol. Additionally, nanocarriers, such as liposomes and dendrimers, improve drug delivery efficacy. Another frontier is anti-plasmid strategies aiming to combat antimicrobial resistance (AMR). Plasmid curing methods, although mostly tested "in vitro," show promise in reducing AMR gene prevalence. Chemical agents and genetic engineering tools like CRISPR-Cas systems offer innovative approaches. Furthermore, antivirulence compounds target bacterial pathogenicity pathways, reducing virulence without affecting bacterial viability. Quorum-sensing inhibitors, such as flavonoids and lactonases, disrupt bacterial communication systems, offering new avenues for combating bacterial infections. Antivirulence compounds act at multiple levels, including host immune modulation and targeting virulence factors like Type Three Secretion Systems (T3SSs), thereby providing a multifaceted approach to address antibiotic resistance.
Unconventional Strategies
Unconventional strategies for combating AMR include exploring alternative drug classes such as antihistamines, anesthetics, and cardiovascular drugs, as well as fecal microbiota transplantation (FMT) for restoring gut microbiota diversity. FMT has shown promising results in treating recurrent Clostridium difficile infections by replenishing healthy gut bacteria and displacing antibiotic-resistant pathogens.
Conclusion
Antimicrobial resistance remains an urgent global health threat, necessitating collaborative efforts and innovative approaches for effective mitigation. Spanning from conventional antibiotics to cutting-edge therapies, researchers are charting a diverse array of strategies to overcome antimicrobial resistance and safeguard public health. Through interdisciplinary collaboration and a commitment to innovation, we can aspire to mitigate the impact of AMR and ensure the sustained efficacy of antimicrobial agents for generations to come.
Reference
- Murugaiyan J., et al. Progress in alternative strategies to combat antimicrobial resistance: Focus on antibiotics. Antibiotics. 2022, 11(2): 200.
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