Warnings of the existential threat posed by growing antimicrobial resistance (AMR) are now common in scientific literature, international and industry trade association output, and in the popular press, with even insurance companies adding a voice1. Published estimates of the impact of AMR differ in methodology and scope, but all make for sober reading. The widely cited findings of the Global Research on Antimicrobial Resistance (GRAM) project, which modelled AMR impact across 204 countries, forecasts 39m AMR-related deaths between 2025 and 2050, or around three deaths per minute – a 74.5% (from AMR associated deaths of 4.71m in 2021 to 8.22m deaths in 2050)2.
The drivers of AMR are readily identifiable but complex. While unnecessary antibiotic consumption through inappropriate prescribing is a major factor, likewise excessive antibiotic use in food-producing animals, sociodemographic, health-related, and environmental risk factors also contribute3. The burden of AMR falls most heavily on low and middle-income countries, with self-medication, weak healthcare infrastructure, and poor infection control fanning the flames4.
While the rate and scale of AMR emergence owe much to human fecklessness, evolutionary biology has always meant the inevitable loss of antibiotic usefulness. Random mutations confer resistance, the effect of which is amplified through selection by antibiotic exposure.
Bacterial resistance arises through a variety of mechanisms:
Resistance traits can be acquired through plasmid-mediated genetic transfer between commensal and disease-causing bacteria. History tells us that the introduction of each new class of antibiotic is swiftly followed by clinical failure and laboratory confirmation of resistance5.
Ingenuity and commercial endeavour have failed to outpace nature in the AMR arms race. Until 2025, no new class of antibiotic had been introduced in three decades, with advances confined to the modification of a small number of known chemical scaffolds.
Biological complexity and commercial unattractiveness - why spend hundreds of millions of dollars developing a drug when sales will be constrained by the need to conserve its usefulness? - have precipitated a mass withdrawal from antibiotic R&D by global pharmaceutical companies, along with casualties among speciality biopharma. Achaogen achieved first year sales of only around $1m for plazomicin (Zemdri®) a treatment for urinary tract infection, tipping the company into liquidation. Tetraphase won marketing approval for eravacycline but struggled to establish its superiority over other antibiotics. Once valued at close to $2bn, the company was acquired for less than $50m.
Technical and commercial barriers have made for a worryingly slender development pipeline. In its October 2025 analysis7, the World Health Organization identified 90 antibacterials or combinations which included at least one new therapeutic entity with activity against either WHO-defined "bacterial priority pathogens" (BPP)8, Clostridioides difficile or Helicobacter pylori, in clinical development as of February 2025, down from the 97 antibacterials recognised in the previous year.
To place that figure in context: the global pharmaceutical pipeline contains approximately 23,000 drug candidates9, of which oncology alone accounts for over 8,000. Cancer claims around 18 lives per minute globally10; AMR, at approximately 3 deaths per minute, represents roughly one-sixth of that toll.
Of the 90 candidates, 50 were considered "traditional" (directly acting small molecules), the remainder being "non-traditional", representing yet to be validated modalities and encompassing peptides, antibodies, anti-virulence agents, bacteriophages, phage-derived enzymes, oligonucleotides, and microbiome-modulating agents. Only three candidates were under regulatory review, with 14 in Phase II/III development and the remaining 73 at an earlier stage. Six of the traditional candidates represented new chemical classes, with three having new modes of action.
The number of antibiotic approvals over the past 25 years paints a bleak picture, averaging around 2 per year across all territories, with no approvals in some years between 2000 and 20246,11. Recent bright spots include FDA or EMA approvals of four new antibiotics in 2024: Exblifep® (Allecra Therapeutics); Emblaveo® (Pfizer), ORLYNVAH™ (Iterum Therapeutics), and Zevtera® (Basilea Pharmaceutica).
This year (2025) witnessed that great rarity, approval of a first-in-class antibiotic, Blujepa® (gepotidacin: GSK) for the treatment of uncomplicated urinary tract infections (UTI), with the prospect of label expansion to uncomplicated gonorrhoea treatment before year end. Zoliflodacin (Innovia Speciality Therapeutics, originally developed by AstraZeneca and acquired along with Entasis Therapeutics), another first-in-class agent, is under review for the same indication.
Antibiotic development is almost entirely absent from the 2025 clinical pipelines of the 20 largest pharma companies (by 2024 revenue). GSK is an exception, with tebipenem HBr, a promising oral carbapenem licenced from Spero Therapeutics in Phase III development for complicated UTI (cUTI), and two first-in-class tuberculosis treatments, ganfeborole and alpibectir, (licenced from BioVersys AG), with development supported by European Union funding. Roche has initiated a Phase III study of zosurabalpin, a first-in-class antibiotic discovered by Harvard researchers and active against drug-resistant Acinetobacter baumannii, a major cause of hospital-acquired infection.
Both Spero Therapeutics and BioVersys sport other antibiotic assets: the former SPR720, indicated in non-tuberculosis pulmonary mycobacterial disease, currently on hold after Phase II completion, and the latter BV100, a repurposed small molecule with activity against A. baumannii. Spero's tebipenem HBr partner for Asia, Meiji Seika Pharma, has a long history of antibiotic manufacture and is developing OP0595 (nacubactam), a novel β-lactamase inhibitor.
Shionogi, a mid-tier Japanese pharma, has invested heavily in anti-infective R&D, acquiring a small biotech, Qpex in 2018 to give the company a US development hub. Its lead programs are evaluating the combination of a Qpex invented asset, xeruborbactam a β-lactamase inhibitor, with Shionogi's cefiderocol (approved in the US as Fetroja®) for Gram-negative bacterial infections, and S-743229, an oral pro-drug of xeruborbactam, with Shionogi-developed ceftibuten for cUTI.
India's Wockhardt has submitted WCK 5222 (zidebactam/cefepime: Zaynich™) for approval in the US as a cUTI treatment. Another candidate, WCK 4282 (cefepime/tazobactam) aimed at hospital-acquired Gram-negative infection is in Phase III development. BWC0977 (Bugworks Research), a novel topoisomerase inhibitor in Phase I development has both broad-spectrum activity and is amenable to both intravenous and oral formulation.
Basilea Pharmaceutics rescued ceftibuten-ledaborbactam etzadroxil from its developers Venatorx Pharmaceuticals and Melinta Therapeutics (recently acquired by Cormedix) following rejection by the FDA due to manufacturing issues. Basilea hopes to register the drug as a new cUTI treatment. An early-stage candidate, BAL2420 is a first-in-class LptA inhibitor aimed at antibiotic-resistant Gram-negative bacteria.
Debiopharm's afabicin (Debio 1450, acquired with Affinium Pharmaceuticals), a first-in-class fatty acid biosynthesis inhibitor, is in Phase II study in staphylococcal bone infection. China's TenFor Therapeutics is also targeting staphylococcal infection with an oral pro-drug/co-drug rifaquizinone (TNP-2092) which is cleaved to give two antibacterial agents, a rifamycin derivative, and a quinolone antibiotic.
Small molecule antibiotics offer convenience of dosing in community and hospital settings, predictable pharmacokinetics and bioavailability and crucially broad-spectrum activity, invaluable in first-line empirical use. A variety of "non-traditional" antibiotics which exploit different vulnerabilities to those targeted by conventional antibiotics are in development and might potentially result in treatments effective in multi-drug-resistant (MDR) infections, and either synergise with or even replace traditional antibiotics in certain infections.
Bacteriophage, naturally occurring lytic viruses with exquisite sensitivity for their target, feature large in the WHO analysis, with candidates from Armata Pharmaceuticals, BiomX and Technophage in development for P. aeruginosa infection, and others for S. aureus and Gram-negative infections. Phage therapy has been explored for close to a century and recent case studies and limited controlled clinical trial data indicate that clinically meaningful infection control can be achieved even in MDR infections12.
However, mainstream use is hamstrung through the critical requirements of effective (and safe) phage selection, scale-up and manufacture of a pharmaceutically acceptable consistent product of known potency and stability. Phage cocktails have been employed to circumvent narrow specificity, but their composition remains empirical. Gaps in treatment-related phage biology (rate of resistance onset, phage-antibiotic interaction, host immune response) confound treatment optimisation13. Enhancement of phage efficacy through CRISPR-Cas gene editing is in early clinical evaluation against E. coli infections (Locus Biosciences and SNIPR Biome)14. Natural or engineered phage-derived enzymes – lysins – offer a simpler and potentially valuable adjunct to antibiotic therapy, although failure of a Phase III study of exebacase in methicillin-resistant S. aureus infection pushed its developer, ContraFect into liquidation.
Antimicrobial peptides (AMPs) have a history of use almost as long as that of phage therapy. Nisin, discovered in the 1920s, still serves as a valuable preservative in canned foods and dairy products. An abundance of AMPs has been identified from natural sources, but their clinical utility has remained elusive. Synthetic peptides appear to hold more promise: zosurabalpin (Roche/Harvard), is currently in Phase III development; voxvoganan (Amicoat, a Lytix spin-out) is under evaluation as an infection-preventing medical device coating, and peceleganan (ProteLight Pharma), is close to registration in China for the topical treatment of wound infections. Peptilogics recently closed a Series B2 round of $78m to progress evaluation of zaloganan (PLG0206) in the reduction of prosthetic joint infections. Omnix Medical closed a $25 million Series C round to take its antimicrobial peptide OMN6, an engineered version of a peptide found in silk moths, through Phase II evaluation against MDR Gram-negative pathogens.
Disarming bacteria through targeting virulence factors has the potential to alleviate disease without exerting selective pressure on the causative organism. Zinplava™ (bezlotoxumab: Merck) a since discontinued monoclonal antibody specific for C. difficile toxin B was approved in 2016. AZD5148 (AstraZeneca), a toxin B specific antibody, is in early clinical development. Salvecin® (AR-301, tosatoxumab: Aridis Pharmaceuticals), a S. aureus α-toxin specific fully human antibody is in late-stage study as an adjunct to antibiotic therapy in ventilator-associated pneumonia (VAP), with another α-toxin candidate, AR-320 under evaluation as a prophylactic agent in VAP.
Biofilms, a complex extracellular matrix composed of proteins, lipids, nucleic acids and secondary metabolites provide a growth-friendly environment while shielding bacteria from exposure to antibiotics. Monoclonal antibodies targeting DNABII protein, crucial in the maintenance of biofilm integrity, are under evaluation in prosthetic joint infection (calpurbatug: Trellis Biosciences) and in chronic P. aeruginosa infection (CMTX-101: Clarametyx Biosciences). Small molecule antivirulence agents include GSK's GSK3882347, an E. coli FimH adhesin inhibitor, in early study in uncomplicated UTI, and ALS-4, an inhibitor of staphyloxanthin, a key protective factor expressed by S. aureus in soft tissue infection.
Antibiotic disruption of the gut microbiome (dysbiosis) is a contributory factor in C. difficile infection (CDI) and recurrence. The live biotherapeutic (LBT) products REBYOTA® (Ferring), donor-derived live faecal bacteria administered as an enema, and Vowst®, an oral faecal bacteria spore suspension (Nestlé Health Science) approved for CDI recurrence. Other LBTs in the pipeline include VE303 (Vedanta Biosciences), a "consortium" product comprising eight commensal bacteria strains; MET-2 (NuBiyota/Takeda), a 40-strain consortium product, and MBK-01 (Mikrobiomik), a lyophilised donor microbiota product.
Small to mid-tier companies are almost exclusively at the forefront of antibacterial development. While innovation is not in short supply, small biopharma is vulnerable to the waxing and waning of life science investment. Public sector, public-private, industry consortia, and not-for-profit funding is keeping antimicrobial development alive, although this collective generosity currently equates to less than 1% of the estimated $223bn annual expenditure on cancer research and development15.
Major contributors include: the Biomedical Advanced Research and Development Authority (BARDA), a US agency within the Department of Health and Human Services and a contributor to GSK's gepotidacin and Basilea's BAL2420 development programs; the US National Institute of Allergy and Infectious Diseases (NIAID), an important enabler of much preclinical research; the Global Antibiotic Research and Development Partnership (GARDP), a now independent not-for-profit originating with the WHO and the Drugs for Neglected Diseases Initiative and a contributor to zoliflodacin development; Novo Holdings' Replenishing and Enabling the Pipeline for Anti-Infective Resistance (REPAIR) Impact Fund; and the AMR Action Fund, with contributors including the WHO, the European Investment Bank, the Wellcome Trust, and an array of international biopharmaceutical companies.
Several of these funding bodies, together with the Bill and Melinda Gates Foundation, The Global AMR Innovation Fund, and the governments of Germany, Italy, Japan, Canada and the UK contribute to the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), originally conceived as a means of preserving and progressing underfunded or abandoned early-stage AMR-fighting assets.
CARB-X therapeutic "graduates" – those progressing in the clinic, include candidates from Peptilogics, Trellis Bioscience, Clarametyx Biosciences and GSK. Importantly, CARB-X is technology-agnostic, supporting traditional and non-traditional antibacterials, vaccines against the problem pathogens N. gonorrhoeae and K. pneumoniae, and rapid diagnostics for bacterial infections and susceptibility testing. The UK's more modestly funded Pathways to Antimicrobial Clinical Efficacy (PACE) initiative has a similar early stage, all technologies strategy. To mark "World Antimicrobial Resistance Awareness Week" 2025, GSK has pledged £45m to the academic research-focused Fleming Initiative to promote the use of AI in antibiotic discovery among other projects.
Regulatory incentives aimed at preserving and expanding industrial antimicrobial development vary by region, with different approaches to expedited pathways and market incentives.
The US Generating Antibiotic Incentives Now (GAIN) Act of 2012 adds five years of market exclusivity along with fast-track status and priority review for "qualified infectious disease products" (QIDP) which aim to address serious unmet need. The Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) pathway (2016) is aimed at expediting approval for drugs intended for high-need special populations without evidence from large clinical studies. In Europe, the PRIority MEdicines (PRIME) scheme offers developers early, enhanced regulatory guidance and accelerated marketing submission review, with small companies being eligible for Early Entry PRIME on the back of proof of principle data.
While the need for "pull" incentives which recognise the imbalance between the cost of new antimicrobial development and market return is widely recognised, implementation of mutually beneficial purchasing schemes is lacking. The UK launched a pilot subscription scheme in 2022 with NHS (England) guaranteeing fixed annual payment to two companies for a period of 10 years, now being extended nationwide and for additional antibiotics.
While the value of the UK scheme is debated, it is seen as offering encouragement for broader adoption of other delinked pricing models, such as the yet to be ratified Putting the Pioneering Antimicrobial Subscriptions To End Upsurging Resistance (PASTEUR) Act, whereby the US government would enter into contracts with antibiotic manufacturers. The European Union has proposed a much criticized "transferable exclusivity voucher" scheme, where antimicrobial developers can opt to benefit from an additional one year of market exclusivity or otherwise sell the voucher.
Evolutionary biology dictates that we may never counter AMR, but there is much that can be done to ensure that we are never completely outpaced. Innovation, and its continued financial incentivisation, are vital. Recent first-in-class antibiotic approvals are encouraging, but the discovery of new scaffolds and targets with a low propensity to mutate are needed, along with a deeper understanding of bacterial systems biology through genome-scale metabolic modelling. As in other areas of drug development, much is expected from the application of AI/ML16. There are few approved classes of antifungal drugs, and there is increasing threat from both resistance and emerging fungal pathogens. The WHO fungal pathogen priority list now runs to 19 organisms17.
There is no mystery around how the selective pressures which generate AMR can be lessened: appropriate prescribing; antibiotic stewardship; public and healthcare professional education, and minimising use in food animals. Greater uptake of currently licenced vaccines, both bacterial (S. pneumoniae, Haemophilus influenzae, Neisseria meningitidis) and viral (influenza, respiratory syncytial virus, COVID-19) can reduce community antibiotic prescribing. Global adoption of AMR reduction practices is daunting: antibiotic consumption continues to rise in middle and low-income countries under the pressures of poor infrastructure and healthcare access, inadequate surveillance, higher disease burdens, and low vaccination rates. Inaction is not an option: AMR does not recognize country borders.
Antibiotics are uniquely societal drugs because individual use affects others in the community and environment. Better stewardship, incentives, and establishment of a special regulatory category will improve how they are used, marketed, and developed through incentives to industry.
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