The domain of antimicrobials serves as a foundational cornerstone in the annals of medicine, reshaping the landscape of disease management since its inception. From the fortuitous discovery of penicillin to the modern synthesis of potent antibacterial agents, the trajectory of antimicrobials reflects a profound narrative of scientific inquiry and medical advancement. However, amidst this narrative of triumph lies the ominous specter of antimicrobial resistance (AMR), a formidable challenge confronting contemporary healthcare systems. In this discourse, we embark on an odyssey through the intricate realm of antimicrobial peptides (AMPs), seeking to unravel their enigmatic allure and therapeutic promise against the backdrop of burgeoning antimicrobial resistance.
From Ancient Remedies to Synthetic Marvels
The chronicles of antimicrobials trace back to ancient civilizations, where empiric remedies such as herbal concoctions and moldy substances were wielded against microbial adversaries. The genesis of modern antimicrobial therapy burgeoned with Paul Ehrlich’s quest for a ‘magic bullet’ to selectively target pathogens, culminating in the synthesis of arsphenamine in 1909. Subsequently, the fortuitous discovery of penicillin by Sir Alexander Fleming in 1928 heralded a paradigm shift, catalyzing the era of antibiotics. Over the ensuing decades, relentless scientific pursuit has yielded a plethora of essential antimicrobials, underscoring their indispensable role in modern healthcare.
Paul Ehrlich discovered “salvarsan” or arsphenamine which has long been used to treat syphilis. This disease is caused by the spirochete Treponema pallidum.
The discovery of penicillin in 1928 started the golden age of natural product antibiotic discovery that peaked in the mid-1950s.
The Menace of Antimicrobial Resistance
Despite their pivotal role in combating infectious diseases, antibiotics face an existential threat in the form of antimicrobial resistance. Exacerbated by rampant misuse and overuse, antimicrobial resistance has precipitated a perilous conundrum, jeopardizing the efficacy of our therapeutic arsenal. Multidrug-resistant pathogens, exemplified by the emergence of Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, loom ominously, presenting formidable challenges in clinical management. The inexorable evolution of resistance mechanisms underscores the urgent imperative for innovative therapeutic modalities.
Mechanisms of P. aeruginosa biofilm-mediated antibiotic resistance. Yi, E-J. & Kim, A-J. (2023). Antimicrobial and Antibiofilm Effect of Bacteriocin-Producing Pediococcus inopinatus K35 Isolated from Kimchi against Multidrug-Resistant Pseudomonas aeruginosa. Antibiotics 2023, 12(4), 676; doi: https://doi.org/10.3390/antibiotics12040676.
Bacterial Survival Stratagems
Bacteria, quintessential survivors of the microbial world, have evolved an arsenal of sophisticated survival mechanisms, confounding conventional antimicrobial strategies. The triad of resistance, tolerance, and persistence engenders resilience in the face of antimicrobial onslaught, perpetuating the cycle of infection and treatment failure. The ascendancy of multidrug-resistant strains, spanning both acquired and opportunistic pathogens, portends dire ramifications for global health security, necessitating a paradigmatic shift in therapeutic paradigms.
Uluseker, C., Kaster, K.M., Thorsen, K., Basiry, D., Shobana, S., Jain, M., Kumar, G., Kommedal, R. & Pala-Ozkok, I. (2021). A Review on Occurrence and Spread of Antibiotic Resistance in Wastewaters and in Wastewater Treatment Plants: Mechanisms and Perspectives.Frontiers of Microbiology, 12:717809. doi: 10.3389/fmicb.2021.717809.
AMPs: Agents of Therapeutic Revolution
Amidst the escalating crisis of antimicrobial resistance, antimicrobial peptides (AMPs) emerge as veritable harbingers of therapeutic innovation. Endowed with multifaceted mechanisms of action and broad-spectrum activity, AMPs represent a promising frontier in antimicrobial therapy. Unlike conventional antibiotics, AMPs leverage diverse strategies, ranging from membrane disruption to immunomodulation, rendering them less prone to resistance development. Their innate versatility and potent antimicrobial efficacy position AMPs as formidable contenders in the battle against multidrug-resistant pathogens.
Antimicrobial mechanism of antimicrobial peptides (AMPs). It includes the cell wall–targeting mechanism, membrane-targeting mechanism (only agglutination model is listed), translocation mechanism, and intracellular mechanism of intracellular activity. The blue arrow and yellow line indicate the process, and a short line at the bottom of the yellow line indicates the inhibition (the same above). Luo, Ying, and Yuzhu Song. 2021. “Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities” International Journal of Molecular Sciences 22, no. 21: 11401. https://doi.org/10.3390/ijms222111401.
Summary of the targets, typical AMPs, and specific action modes of AMPs. Luo, Ying, and Yuzhu Song. 2021. “Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities” International Journal of Molecular Sciences 22, no. 21: 11401. https://doi.org/10.3390/ijms222111401.
Formation process of biofilms and antibiofilm mechanism of AMPs. The formation of biofilm includes four stages: the aggregation or attachment of microorganisms, microbial adhesion, development, and maturation of biofilm, and aging of biofilm. AMPs can act on these processes to perform biological functions. Upregulation and downregulation of genes are indicated by ↑ and ↓. The AMPs in brackets correspond to the corresponding mechanism types. Luo, Ying, and Yuzhu Song. 2021. “Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities” International Journal of Molecular Sciences 22, no. 21: 11401. https://doi.org/10.3390/ijms222111401.
Characterization and Classification of AMPs
The classification of antimicrobial peptides poses a formidable challenge, owing to their structural heterogeneity and multifaceted modes of action. The antimicrobial peptide database (APD) serves as a repository of diverse peptide sequences, encompassing a spectrum of physicochemical properties and functional attributes. From length and net charge to hydrophobicity and post-translational modifications, the intricate interplay of these parameters elucidates the structural and functional diversity inherent to AMPs.
Classification of antimicrobial peptides. Huan. Y., Kong, Q., Mou, H. & Yi, H. (2020). Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields. Frontiers in Microbiology 11:582779. doi: 10.3389/fmicb.2020.582779.
Synthesis and Design of Antimicrobial Peptides
Advances in peptide synthesis methodologies have heralded a new era in the design and optimization of antimicrobial peptides. From natural sources to rationally designed analogs, researchers explore a myriad of avenues to harness the therapeutic potential of AMPs. Post-translational modifications further augment the efficacy and stability of AMPs, accentuating their utility as next-generation antimicrobial agents. By amalgamating synthetic prowess with structural insights, researchers endeavor to unlock the full therapeutic potential of AMPs, charting a course toward a renaissance in antimicrobial therapy.
Different structures of AMPs.(A) LL-37 adopts a typical α-helical conformation (10.2210/pdb2K6O/pdb). (B) Gomesin is a β-sheet peptide and stabilized by disulfide bonds (10.2210/pdb1KFP/pdb). (C) Indolicidin is a AMP with linear extension structure instead of well-defined 3D structure (10.2210/pdb1G89/pdb). (D) α1-purothionin adopts both alpha-helix and beta-sheet conformation, and arrows indicate extension direction (10.2210/pdb2plh/pdb). Huan. Y., Kong, Q., Mou, H. & Yi, H. (2020). Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields. Frontiers in Microbiology 11:582779. doi: 10.3389/fmicb.2020.582779.
Securing Global Health
In the crucible of antimicrobial resistance, the saga of antimicrobial peptides unfolds as a testament to scientific ingenuity and therapeutic resilience. As we navigate the turbulent waters of microbial warfare, AMPs stand poised at the vanguard of therapeutic innovation, offering a glimmer of hope amidst the encroaching shadows of resistance. By unraveling the mysteries of AMPs and harnessing their innate potential, we embark on a transformative odyssey towards a future fortified against the scourge of antimicrobial resistance, ensuring the preservation of global health security for generations to come.
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