Strategies for Combating the Global Health Threat of Antibiotic Resistance: Novel Therapeutics and Combination Approaches
DOI:
https://doi.org/10.22270/ajprd.v14i01.1707Abstract
Background: Antibiotic resistance represents one of the most pressing global public health crises of the 21st century. The increasing prevalence of multidrug-resistant (MDR) bacterial pathogens has significantly reduced the clinical efficacy of existing antimicrobial therapies, resulting in prolonged hospitalizations, increased healthcare costs, and higher morbidity and mortality rates.
Objective: This review critically examines the molecular mechanisms underlying antibiotic resistance and explores emerging therapeutic strategies designed to overcome resistance and restore antibiotic efficacy.
Methods: A comprehensive analysis of recent scientific literature was conducted to evaluate advances in antimicrobial discovery, resistance-modifying strategies, host-directed therapies, and combination approaches.
Results: Resistance mechanisms include enzymatic drug inactivation, target modification, efflux pump overexpression, permeability alterations, and horizontal gene transfer. Emerging interventions such as quorum-sensing inhibitors, bacteriophage therapy, antimicrobial peptides, nanobiotics, CRISPR-Cas systems, immunotherapeutic agents, and photodynamic therapy demonstrate promising potential in combating resistant pathogens.
Conclusion: Although innovative strategies offer hope, challenges including regulatory barriers, economic limitations, and potential resistance evolution persist. A multidisciplinary, globally coordinated approach integrating antimicrobial stewardship, novel therapeutics, and policy reforms is essential to mitigate the antibiotic resistance crisis.
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References
World Health Organization. Global action plan on antimicrobial resistance. Geneva: WHO; 2015.
Murray CJL, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet. 2022;399(10325):629–655.
O'Neill J. Tackling drug-resistant infections globally: Final report and recommendations. London: Review on Antimicrobial Resistance; 2016.
Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. P T. 2015;40(4):277–283.
Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010;74(3):417–433.
Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 2015;13(1):42–51.
Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol Spectr. 2016;4(2):1–37.
Fleming A. On the antibacterial action of cultures of Penicillium. Br J Exp Pathol. 1929;10(3):226–236.
Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: No ESKAPE! Clin Infect Dis. 2009;48(1):1–12.
Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research and development of new antibiotics: WHO priority list. Lancet Infect Dis. 2018;18(3):318–327.
Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis. 2013;13(12):1057–1098.
Wright GD. Something old, something new: Revisiting natural products in antibiotic drug discovery. Can J Microbiol. 2014;60(3):147–154.
Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009;325(5944):1089–1093.
Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: Confronting antibiotic resistance. Nat Rev Drug Discov. 2007;6(1):29–40.
Lewis K. Platforms for antibiotic discovery. Nat Rev Drug Discov. 2013;12(5):371–387.
Brown ED, Wright GD. Antibacterial drug discovery in the resistance era. Nature. 2016;529(7586):336–343.
Wright GD. The antibiotic resistome: The nexus of chemical and genetic diversity. Nat Rev Microbiol. 2007;5(3):175–186.
Koonin EV, Makarova KS. CRISPR-Cas: Evolution of adaptive immunity. Nat Rev Microbiol. 2019;17(6):331–345.
Bikard D, Barrangou R. Using CRISPR-Cas systems as antimicrobials. Nat Biotechnol. 2017;35(3):225–233.
Czaplewski L, Bax R, Clokie M, et al. Alternatives to antibiotics. Lancet Infect Dis. 2016;16(2):239–251.
Abedon ST, García P, Mullany P, Aminov R. Phage therapy: Past, present and future. Front Microbiol. 2017;8:981.
Chan BK, Abedon ST, Loc-Carrillo C. Phage cocktails and resistance development. Future Microbiol. 2013;8(6):769–783.
Hancock REW, Sahl HG. Antimicrobial peptides and host-defense peptides. Nat Biotechnol. 2006;24(12):1551–1557.
Mahlapuu M, Håkansson J, Ringstad L, Björn C. Antimicrobial peptides: An emerging category of therapeutic agents. Front Cell Infect Microbiol. 2016;6:194.
Rai M, Deshmukh SD, Ingle AP, Gade AK. Silver nanoparticles as new antimicrobials. Biotechnol Adv. 2012;30(1):46–56.
Pelgrift RY, Friedman AJ. Nanotechnology as a therapeutic tool to combat microbial resistance. Adv Drug Deliv Rev. 2013;65(13-14):1803–1815.
Ventola CL. The antibiotic resistance crisis: Part 2: Management strategies. P T. 2015;40(5):344–352.
Rutherford ST, Bassler BL. Bacterial quorum sensing. Cold Spring Harb Perspect Med. 2012;2(11):a012427.
Kalia VC. Quorum sensing inhibitors: An overview. Biotechnol Adv. 2013;31(2):224–245.
Davies D. Understanding biofilm resistance. Nat Rev Drug Discov. 2003;2(2):114–122.
Hoiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents. 2010;35(4):322–332.
Wright GD. Antibiotic adjuvants: Rescuing antibiotics from resistance. Trends Microbiol. 2016;24(11):862–871.
Bush K, Bradford PA. β-Lactams and β-lactamase inhibitors. Cold Spring Harb Perspect Med. 2016;6(8):a025247.
Li XZ, Plesiat P, Nikaido H. Efflux-mediated antimicrobial resistance. Drugs. 2015;75(14):1555–1623.
Poole K. Efflux pumps as antimicrobial resistance mechanisms. J Antimicrob Chemother. 2005;56(1):20–51.
WHO. 2023 antibacterial agents in clinical and preclinical development: An overview and analysis. Geneva: WHO; 2023.
Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med. 2013;368(4):299–302.
Rossolini GM, Arena F, Pecile P, Pollini S. Update on antibiotic resistance crisis. Lancet Infect Dis. 2014;14(12):125–133.
Fair RJ, Tor Y. Antibiotics and bacterial resistance. Perspect Medicin Chem. 2014;6:25–64.
Clatworthy AE, Pierson E, Hung DT. Targeting virulence. Nat Chem Biol. 2007;3(9):541–548.
Andersson DI, Hughes D. Microbiological effects of sublethal antibiotic levels. Nat Rev Microbiol. 2014;12(7):465–478.
Aminov RI. A brief history of the antibiotic era. Front Microbiol. 2010;1:134.
Brown SP, Cornforth DM, Mideo N. Evolution of virulence. Philos Trans R Soc Lond B Biol Sci. 2012;367(1590):1865–1878.
Tang SS, Apisarnthanarak A, Hsu LY. Mechanisms of β-lactam resistance. Ann Acad Med Singapore. 2014;43(11):514–523.
Davies J. Where have all the antibiotics gone? Can J Infect Dis Med Microbiol. 2006;17(5):287–290.
Wright GD. Q&A: Antibiotic resistance. J Biol. 2010;9(3):1–5.
Lerminiaux NA, Cameron ADS. Horizontal gene transfer in bacteria. FEMS Microbiol Rev. 2019;43(5):490–518.
Bush K. Past and present perspectives on β-lactamases. Antimicrob Agents Chemother. 2018;62(10):e01076-18.
Tacconelli E, Sifakis F, Harbarth S, et al. Surveillance for control of antimicrobial resistance. Lancet Infect Dis. 2018;18(3):e99–e106.
Singh R, Smitha MS, Singh SP. The role of nanotechnology in combating multidrug resistance. J Nanosci Nanotechnol. 2014;14(7):4745–4756.
Hwang AY, Gums JG. The emergence and evolution of antimicrobial resistance. Clin Ther. 2016;38(6):1234–1247.
Bush K, Courvalin P, Dantas G, et al. Tackling antibiotic resistance. Nat Rev Microbiol. 2011;9(12):894–896.
World Health Organization. Antimicrobial resistance: Global report on surveillance. Geneva: WHO; 2014.
Piddock LJV. The crisis of antibiotic resistance. Clin Microbiol Infect. 2012;18(9):846–853.
Kaur T, Rishi P. Bacteriophage therapy: An alternative approach. Crit Rev Microbiol. 2018;44(1):1–16.
Shankar PR. Book review: The antibiotic era. J Pharmacol Pharmacother. 2016;7(1):46–48.
Makvandi P, Wang CY, Zare EN, Borzacchiello A, Niu L, Tay FR. Metal-based nanomaterials in antimicrobial therapy. Adv Funct Mater. 2020;30(17):1910021.
Ventola CL. The antibiotic resistance crisis: Overview and updates. P T. 2015;40(4):277–283.
Koonin EV, Zhang F. Coupling immunity and genome engineering. Cell. 2017;168(3):377–389.
Laxminarayan R. Antibiotic resistance and stewardship. Clin Infect Dis. 2014;59(Suppl 3):S88–S94.
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