The Dual Crisis: Antibiotic Resistance and the Discovery Void – A Review of Novel Therapeutic Strategies and Non-Traditional Approaches

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Year : 2026 | Volume : 3 | 01 | Page :
    By

    Priyanshu Upadhyay,

  • Ankit Maurya,

  • Anand Prakash,

  1. Professor, P.K. University, Maharashtra, India
  2. Student, P.K. University, Maharashtra, India
  3. Student, S.N. College of Pharmacy, Jaunpur, Uttar Pradesh, India

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: Antibiotic resistance; antimicrobial resistance (AMR); discovery void; novel therapeutics; non-traditional antimicrobials; bacteriophage therapy; antimicrobial peptides; host-directed therapy; microbiome modulation; anti-virulence strategies; CRISPR antimicrobials; nanoparticle therapeutics; synthetic biology; drug discovery.

How to cite this article:
Priyanshu Upadhyay, Ankit Maurya, Anand Prakash. The Dual Crisis: Antibiotic Resistance and the Discovery Void – A Review of Novel Therapeutic Strategies and Non-Traditional Approaches. International Journal of Antibiotics. 2026; 03(01):-.
How to cite this URL:
Priyanshu Upadhyay, Ankit Maurya, Anand Prakash. The Dual Crisis: Antibiotic Resistance and the Discovery Void – A Review of Novel Therapeutic Strategies and Non-Traditional Approaches. International Journal of Antibiotics. 2026; 03(01):-. Available from: https://journals.stmjournals.com/ijab/article=2026/view=236726


References

1. World Health Organization. Global action plan on antimicrobial resistance. Geneva:
WHO Press; 2015.
2. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United
States. Atlanta (GA): U.S. Department of Health and Human Services; 2019.
3. O’Neill J. Tackling drug-resistant infections globally: final report and
recommendations. London: Review on Antimicrobial Resistance, UK Government;
2016.
4. European Centre for Disease Prevention and Control. Antimicrobial resistance in the
EU/EEA: annual epidemiological report 2023. Stockholm: ECDC; 2024.
5. Indian Council of Medical Research. Annual report on antimicrobial resistance
surveillance and research network. New Delhi: ICMR; 2022.
6. Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV. Molecular
mechanisms of antibiotic resistance. Nat Rev Microbiol. 2015;13(1):42–51.
doi:10.1038/nrmicro3380.
7. Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol Spectr.
2016;4(2):VMBF-0016-2015. doi:10.1128/microbiolspec.VMBF-0016-2015.
8. Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance: the need for
coordinated global solutions. Lancet Infect Dis. 2013;13(12):1057–1098.
doi:10.1016/S1473-3099(13)70318-9.

9. Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a multifaceted global
challenge. Pathog Glob Health. 2015;109(7):309–318.
doi:10.1179/2047773215Y.0000000030.
10. Rice LB. Mechanisms of resistance and clinical significance of resistance to β-
lactams, glycopeptides and fluoroquinolones. Mayo Clin Proc. 2012;87(2):198–208.
doi:10.1016/j.mayocp.2011.12.003.
11. Brown ED, Wright GD. Antibacterial drug discovery in the era of resistance. Nature.
2016;529(7586):336–343. doi:10.1038/nature17042.
12. 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.
13. Lewis K. Platforms for antibiotic discovery. Nat Rev Drug Discov.
2013;12(5):371–387. doi:10.1038/nrd3975.
14. Silver LL. Challenges of antibacterial discovery. Clin Microbiol Rev.
2011;24(1):71–109. doi:10.1128/CMR.00030-10.
15. 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.
16. 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.
17. Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage therapy for human bacterial
infections: principles and practice. Bacteriophage. 2011;1(2):66–85.
doi:10.4161/bact.1.2.15845.
18. 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.
19. Pirnay JP, Merabishvili M, Van Raemdonck H, et al. Quality and safety standards for
sustainable bacteriophage therapy products. Pharm Res. 2015;32(7):2173–2179.
doi:10.1007/s11095-014-1617-7.
20. Hyman P. Bacteriophages and their application in phage therapy: isolation,
characterization and host range determination. Pharmaceutics. 2019;11(3):35.
doi:10.3390/pharmaceutics11030035.
21. Hancock REW, Sahl HG. Antimicrobial peptides and host defense peptides as novel
therapeutic strategies. Nat Biotechnol. 2006;24(12):1551–1557. doi:10.1038/nbt1267.
22. Mookherjee N, Anderson MA, Haagsman HP, Davidson DJ. Antimicrobial host
defence peptides: biological functions and clinical potential. Nat Rev Drug Discov.
2020;19(5):311–332. doi:10.1038/s41573-019-0058-8.
23. 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.
24. 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.
25. Hasan J, Crawford RJ, Ivanova EP. Antibacterial surfaces: progress toward next-
generation biomaterials. Trends Biotechnol. 2013;31(5):295–304.
doi:10.1016/j.tibtech.2013.01.017.

26. Bikard D, Euler CW, Jiang W, et al. Exploiting CRISPR-Cas systems to develop
sequence-specific antimicrobials. Nat Biotechnol. 2014;32(11):1146–1150.
doi:10.1038/nbt.3043.
27. Citorik RJ, Mimee M, Lu TK. Sequence-specific antimicrobials using RNA-guided
nucleases. Nat Biotechnol. 2014;32(11):1141–1145. doi:10.1038/nbt.3011.
28. van Belkum A, Bachmann TT, et al. Development roadmap for antimicrobial
susceptibility testing systems. Nat Rev Microbiol. 2019;17(1):51–62.
doi:10.1038/s41579-018-0098-9.
29. Caliendo AM, Gilbert DN, et al. Improved diagnostics for infectious diseases: better
tests, better patient care. Clin Infect Dis. 2013;57(Suppl 3):S139–S170.
doi:10.1093/cid/cit578.
30. 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.
31. Gootenberg JS, Abudayyeh OO, Kellner MJ, et al. Multiplexed and portable nucleic
acid detection using CRISPR-based technologies. Science. 2018;360(6387):439–444.
doi:10.1126/science.aaq0179.
32. Niemz A, Ferguson TM, Boyle DS. Point-of-care nucleic acid testing for infectious
diseases. Trends Biotechnol. 2011;29(5):240–250. doi:10.1016/j.tibtech.2011.01.007.
33. 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.
34. Holmes AH, Moore LSP, Sundsfjord A, et al. Mechanisms and drivers of
antimicrobial resistance. Lancet. 2016;387(10014):176–187. doi:10.1016/S0140-
6736(15)00473-0.
35. Woolhouse M, Ward M, van Bunnik B, Farrar J. Antimicrobial resistance in humans,
animals and the environment. Philos Trans R Soc Lond B Biol Sci.
2015;370(1670):20140083. doi:10.1098/rstb.2014.0083.
36. 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.

Ahead of Print Subscription Review Article
Volume 03
01
Received 28/01/2026
Accepted 30/01/2026
Published 31/01/2026
Publication Time 3 Days
50

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