International Journal of Antibiotics Review Article
The Dual Crisis: Antibiotic Resistance and the Discovery Void – A Review of Novel Therapeutic Strategies and Non-Traditional Approaches
Abstract
The global rise of antimicrobial resistance (AMR) has emerged as one of the most critical public health challenges of the 21st century, threatening to undermine decades of therapeutic success and rendering conventional antibiotic regimens increasingly ineffective. Parallel to the escalating resistance rates is a profound “discovery void,” characterised by a steep decline in the development of new antibiotic classes since the late 20th century. Together, these two interconnected crises create a dual burden that significantly restricts treatment options and increases morbidity, mortality, and economic costs worldwide. This review provides a comprehensive evaluation of the underlying drivers of antibiotic resistance, the stagnation of antimicrobial innovation, and the urgent need for novel therapeutics that bypass the limitations of conventional drug discovery. Further, this paper highlights emerging non- traditional approaches—including bacteriophage therapy, antimicrobial peptides, CRISPR- based antimicrobials, nanoparticles, host-directed therapies, microbiome modulation, and anti-virulence strategies—that offer promising avenues to combat resistant pathogens without accelerating selective pressure. A detailed analysis of technological innovations such as AI- driven drug discovery, metagenomic mining, synthetic biology, and immunotherapeutic advancements is also presented. By integrating classical and alternative strategies, this review underscores the importance of a multifaceted approach to addressing the dual crisis and revitalising the antibiotic development pipeline for sustainable global health.
Keywords
References (36)
- World Health Organization. Global action plan on antimicrobial resistance. Geneva: WHO Press; 2015.
- Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States. Atlanta (GA): U.S. Department of Health and Human Services; 2019.
- O’Neill J. Tackling drug-resistant infections globally: Final report and recommendations. London: Review on Antimicrobial Resistance, UK Government; 2016.
- European Centre for Disease Prevention and Control. Antimicrobial resistance in the EU/EEA: Annual epidemiological report 2023. Stockholm: ECDC; 2024.
- Indian Council of Medical Research. Annual report on antimicrobial resistance surveillance and research network. New Delhi: ICMR; 2022.
- Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV. Molecular mechanisms of antibiotic resistance. Nature Reviews Microbiology. 2014;13(1):42-51. doi:10.1038/nrmicro3380
- Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiology Spectrum. 2016;4(2). doi:10.1128/microbiolspec.vmbf-0016-2015
- Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, et al. Antibiotic resistance—the need for global solutions. The Lancet Infectious Diseases. 2013;13(12):1057-1098. doi:10.1016/s1473-3099(13)70318-9
- Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a global multifaceted phenomenon. Pathogens and Global Health. 2015;109(7):309-318. doi:10.1179/2047773215y.0000000030
- Rice LB. Mechanisms of Resistance and Clinical Relevance of Resistance to β-Lactams, Glycopeptides, and Fluoroquinolones. Mayo Clinic Proceedings. 2012;87(2):198-208. doi:10.1016/j.mayocp.2011.12.003
- Brown ED, Wright GD. Antibacterial drug discovery in the resistance era. Nature. 2016;529(7586):336-343. doi:10.1038/nature17042
- Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: No ESKAPE! Clin Infect Dis. 2009;48(1):1–12. doi:10.1086/595011.
- Lewis K. Platforms for antibiotic discovery. Nature Reviews Drug Discovery. 2013;12(5):371-387. doi:10.1038/nrd3975
- Silver LL. Challenges of Antibacterial Discovery. Clinical Microbiology Reviews. 2011;24(1):71-109. doi:10.1128/cmr.00030-10
- Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for resistant pathogens: Addressing the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6(1):29–40. doi:10.1038/nrd2201.
- Schooley RT, Biswas B, Gill JJ, et al. Development and application of personalized bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa infection. Antimicrob Agents Chemother. 2017;61(7):e00954-17. doi:10.1128/AAC.00954-17.
- Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage. 2011;1(2):66-85. doi:10.4161/bact.1.2.15845
- Lin DM, Koskella B, Lin HC. Phage therapy as an alternative strategy in the era of multidrug resistance. World J Gastrointest Pharmacol Ther. 2017;8(3):162–173. doi:10.4292/wjgpt.v8.i3.162.
- Pirnay JP, Blasdel BG, Bretaudeau L, Buckling A, Chanishvili N, Clark JR, et al. Quality and Safety Requirements for Sustainable Phage Therapy Products. Pharmaceutical Research. 2015;32(7):2173-2179. doi:10.1007/s11095-014-1617-7
- Hyman P. Bacteriophages and their application in phage therapy: Isolation, characterization and host range determination. Pharmaceutics. 2019;11(3):35. doi:10.3390/pharmaceutics11030035.
- Hancock REW, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnology. 2006;24(12):1551-1557. doi:10.1038/nbt1267
- Mookherjee N, Anderson MA, Haagsman HP, Davidson DJ. Antimicrobial host defence peptides: functions and clinical potential. Nature Reviews Drug Discovery. 2020;19(5):311-332. doi:10.1038/s41573-019-0058-8
- Rai M, Yadav A, Gade A. Silver nanoparticles as emerging antimicrobial agents. Biotechnol Adv. 2009;27(1):76–83. doi:10.1016/j.biotechadv.2008.09.002.
- Huh AJ, Kwon YJ. Nanoantibiotics: A new approach to combat infectious diseases using nanomaterials. Int J Nanomedicine. 2011;6:2993–3007. doi:10.2147/IJN.S24693.
- Hasan J, Crawford RJ, Ivanova EP. Antibacterial surfaces: the quest for a new generation of biomaterials. Trends in Biotechnology. 2013;31(5):295-304. doi:10.1016/j.tibtech.2013.01.017
- Bikard D, Euler CW, Jiang W, Nussenzweig PM, Goldberg GW, Duportet X, et al. Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials. Nature Biotechnology. 2014;32(11):1146-1150. doi:10.1038/nbt.3043
- Citorik RJ, Mimee M, Lu TK. Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases. Nature Biotechnology. 2014;32(11):1141-1145. doi:10.1038/nbt.3011
- the JPIAMR AMR-RDT Working Group on Antimicrobial Resistance and Rapid Diagnostic Testing, van Belkum A, Bachmann TT, Lüdke G, Lisby JG, Kahlmeter G, et al. Developmental roadmap for antimicrobial susceptibility testing systems. Nature Reviews Microbiology. 2018;17(1):51-62. doi:10.1038/s41579-018-0098-9
- Caliendo AM, Gilbert DN, Ginocchio CC, Hanson KE, May L, Quinn TC, et al. Better Tests, Better Care: Improved Diagnostics for Infectious Diseases. Clinical Infectious Diseases. 2013;57(suppl3):S139-S170. doi:10.1093/cid/cit578
- Kwong JC, McCallum N, Sintchenko V, Howden BP. Whole-genome sequencing in antimicrobial resistance surveillance. Clin Infect Dis. 2015;61(7):1099–1106. doi:10.1093/cid/civ450.
- Science. doi:10.1126/science
- Niemz A, Ferguson TM, Boyle DS. Point-of-care nucleic acid testing for infectious diseases. Trends in Biotechnology. 2011;29(5):240-250. doi:10.1016/j.tibtech.2011.01.007
- Dyar OJ, Huttner B, Schouten J, Pulcini C. Antimicrobial stewardship: Principles and practice. Clin Microbiol Infect. 2017;23(11):793–798. doi:10.1016/j.cmi.2017.08.026.
- Holmes AH, Moore LSP, Sundsfjord A, Steinbakk M, Regmi S, Karkey A, et al. Understanding the mechanisms and drivers of antimicrobial resistance. The Lancet. 2016;387(10014):176-187. doi:10.1016/s0140-6736(15)00473-0
- Woolhouse M, Ward M, van Bunnik B, Farrar J. Antimicrobial resistance in humans, livestock and the wider environment. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015;370(1670):20140083. doi:10.1098/rstb.2014.0083
- Robinson TP, Bu DP, Carrique-Mas J, et al. Antibiotic resistance as a major One Health challenge. Trans R Soc Trop Med Hyg. 2016;110(7):377–380. doi:10.1093/trstmh/trw048.