Antimicrobial resistance (AMR) is a growing global health crisis, with once-effective antibiotics losing efficacy against infections like salmonellosis, tuberculosis, pneumonia, and gonorrhea. The World Health Organization (WHO) has ranked AMR among the top 10 global health threats and released a priority list of resistant pathogens needing urgent attention.

The 2024 Bacterial Priority Pathogens List (BPPL) includes 15 families of antibiotic-resistant pathogens, categorised as critical, high, or medium priority based on their threat level.

- Critical Priority: Includes Gram-negative bacteria like Acinetobacter baumannii, resistant Enterobacterales, and rifampicin-resistant Mycobacterium tuberculosis—noted for severe infections, gene transfer ability, and high impact in low- and middle-income countries (LMICs).

- High Priority: Includes Salmonella, Shigella, Pseudomonas aeruginosa, Staphylococcus aureus, Neisseria gonorrhoeae, and Enterococcus faecium, due to rising resistance and burden in healthcare and community settings.

- Medium Priority: Covers pathogens like Group A and B Streptococci, Streptococcus pneumoniae, and Haemophilus influenzae, which pose risks in resource-limited areas and among vulnerable populations.

AMR already causes over a million deaths annually and threatens the effectiveness of modern medicine, underscoring the urgent need for new antibiotics and public health measures.

Innovation Without Incentive: The Dilemma in Antibiotic Development

The antibiotics market is caught in a paradox. On one hand, AMR is escalating into a global health crisis; on the other, the economic model underpinning antibiotic development is fundamentally broken.

Antibiotics are typically used for short durations and are often reserved as last-line treatments, making them far less profitable than long-term therapies for chronic diseases. As a result, even when scientific advances—such as AI-assisted drug discovery—yield promising candidates, the path to market success remains steep. Low sales volume, cautious prescribing habits, and the preference for older generics over newer, more expensive drugs have all contributed to an unattractive commercial landscape for developers.

To overcome these challenges, governments and regulatory agencies have introduced a mix of "push" and "pull" incentives. Push incentives, such as early-stage research grants, aim to lower the cost of innovation. Pull incentives, on the other hand, reward successful development outcomes by ensuring a viable market.

In the United States, regulatory tools like the Qualified Infectious Disease Product (QIDP) designation enable companies to fast-track approvals using Phase 2 data, receive priority review (reducing decision times from 10 to 6 months), and gain five additional years of market exclusivity. The UK has implemented a subscription-style payment model that provides fixed annual revenues to antibiotic developers, regardless of sales volume. This de-links profitability from usage, allowing for stewardship without penalizing innovation. The EU is exploring similar strategies, although progress has been gradual.

Still, access remains a major barrier—particularly in low- and middle-income countries (LMICs), where resistance-related deaths are higher than in high-income regions. In response, international efforts are underway to harmonize regulatory pathways and speed up access. The WHO recently designated several national agencies, including the US FDA and the European Medicines Regulatory Network, as WHO-Listed Authorities (WLAs). This enables lower-income countries to rely on established regulatory reviews, lowering costs and reducing delays in accessing new antibiotics.

Together, these push-pull strategies and regulatory harmonization efforts are vital steps toward revitalizing antibiotic development. But to succeed, they must be accompanied by global collaboration, strong stewardship frameworks, and a commitment to equitable access—especially in the countries facing the highest burden of resistance.

What Next-Generation Antibiotics Must Deliver

Looking ahead, innovation must go beyond developing new drugs—it must solve the limitations of traditional antibiotics. Small-molecule antibiotics are easy to manufacture and administer, but they have limitations: they cannot evolve, may lack target specificity, and can trigger immune responses.

Next-generation antibiotics should aim to be:

• Evolvable – capable of adapting in response to bacterial changes;

•  Specific – minimizing disruption to beneficial human microbiota;

• Non-immunogenic – reducing the risk of harmful immune reactions.

These criteria are essential for creating truly future-ready antibiotics.

The Antibiotic Pipeline: Current landscape

Development of new antibiotics has slowed due to poor commercial incentives, but a few promising candidates are in late-stage clinical trials and some have been approved:

1. Afabicin (Debiopharm):
A first-in-class antibiotic targeting Staphylococcus spp., including MRSA, in Phase 2 trials for bone and joint infections and acute bacterial skin infections. It has shown strong efficacy and tolerability with no resistance observed in Phase 2 studies.

2. Exblifep (cefepime/enmetazobactam, Allecra Therapeutics):
Recently approved in the EU and US for complicated UTIs, this fixed-dose β-lactam/β-lactamase inhibitor combo shows superiority over piperacillin-tazobactam.

3. Gepotidacin (GSK):
A first-in-class, oral triazaacenaphthylene antibiotic now FDA-approved for uncomplicated urinary tract infections (uUTIs) in females and adolescents (≥12 years, ≥40 kg). Discovered by GSK, Blujepa exhibits a novel mechanism inhibiting bacterial DNA replication via dual Type II topoisomerase binding. The drug is designed with a lower potential for resistance development, offering broad activity against E. coli, S. saprophyticus, and N. gonorrhoeae.

4. Ibezapolstat (Acurx Pharmaceuticals):
An oral antibiotic for C. difficile infections, currently in Phase 2 trials. It targets DNA polymerase IIIC, showing promising efficacy with minimal microbiome disruption.

5. Murepavadin (Spexis):
A pathogen-specific antibiotic targeting Pseudomonas aeruginosa, currently reformulated as an inhaled version (iMPV104) for lung infections in cystic fibrosis patients, in Phase 1.

6. Nacubactam (Meiji Seika):
A Phase 3-ready β-lactamase inhibitor with a dual mechanism effective against resistant infections like CRE, especially in combination with meropenem. It has demonstrated strong efficacy and safety in early trials and holds Fast Track and QIDP status.

7. Nafithromycin (Wockhardt):
Recently approved in India as Miqnaf for treating adult CABP. It’s a novel macrolide offering a 3-day, once-daily oral treatment effective against multi-drug resistant (MDR) pathogens.

8. Sulopenem etzadroxil / probenecid (Iterum Therapeutics):
FDA-approved as Orlynvah for uUTIs in adult women with limited treatment options, this novel oral penem shows potent activity against Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis 

9. Tebipenem pivoxil HBr (GSK/Spero):
An oral carbapenem in Phase 3 for complicated UTIs and acute pyelonephritis; it could become the first oral carbapenem approved in the U.S. and has received QIDP and Fast Track designations.

10. TNP-2092 (TenNor Therapeutics):
A conjugated antibiotic with a multi-target mechanism effective against biofilm-related infections, including prosthetic joint infections. It has completed five Phase 1/2 trials and is advancing to Phase 3.

11. Zoliflodacin (GARDP/Innoviva):
A first-in-class oral antibiotic in Phase 3 for uncomplicated gonorrhoea, effective against MDR Neisseria gonorrhoeae, with a novel mechanism and no cross-resistance with other antibiotics.

Reviving the Pipeline: How Collaborative Commitment Can Sustain Antimicrobial Innovation

The future of antibiotic and antifungal innovation hinges on a shared commitment between small innovators and large pharmaceutical companies. While small- and medium-sized enterprises (SMEs) are driving early-stage breakthroughs, they lack the capacity to scale and deliver global access—especially in low- and middle-income countries. Without the active involvement of big pharma in late-stage development, commercialization, and access planning, promising innovations risk stalling before reaching the patients who need them most.

Public and philanthropic partnerships like the Global Antibiotic Research and Development Partnership (GARDP) help fill this gap, but they cannot bear the burden alone. Sustainable impact demands that large pharmaceutical companies re-engage—not just through financial contributions, but through meaningful collaboration and commercial support.

Reviving antimicrobial R&D is not only a public health imperative but also a strategic necessity to protect the broader pharmaceutical ecosystem, including the viability of treatments like cancer therapies that rely on effective antibiotics.

References

1. Strich JR, Mishuk A, Diao G, et al. Assessing clinician utilization of next-generation antibiotics against resistant gram-negative infections in U.S. hospitals: a retrospective cohort study. Ann Intern Med. 2024;177(5):559-572. doi:10.7326/M23-2309

2. Wasan H, Reeta KH, Gupta YK. Strategies to improve antibiotic access and a way forward for lower middle-income countries. J Antimicrob Chemother. 2024;79(1):1-10. doi:10.1093/jac/dkad291

3. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655. doi:10.1016/S0140-6736(21)02724-0

4. World Health Organization. List of WHO-listed authorities (WLAs). May 2024. Accessed April 8, 2025. https://cdn.who.int/media/docs/default-source/medicines/regulatory-systems/wla/list_of_wla_may24.pdf?sfvrsn=1f6c2140_32&download=true

5. Access to Medicine Foundation. Are Pharma Companies Addressing Global Health Needs? R&D report. Accessed April 8, 2025. https://accesstomedicinefoundation.org/medialibrary/access-to-medicine-foundation_r&d-report.pdf

6. Shim H. Three innovations of next-generation antibiotics: evolvability, specificity, and non-immunogenicity. Antibiotics (Basel). 2023;12(2):204. doi:10.3390/antibiotics12020204

7. World Health Organization. 2024 WHO Bacterial Priority Pathogens List to Guide Research, Development and Strategies to Combat Antimicrobial Resistance. 2024. Accessed April 8, 2025. https://iris.who.int/bitstream/handle/10665/376776/9789240093461-eng.pdf?sequence=1

C&EN. New antibiotics are hard to come by. Red tape is making the problem worse. Chem Eng News. 2024