Beyond antibiotics: which antimicrobial alternatives are actually ready for the clinic?

Antimicrobial resistance already kills. In 2019, resistant infections were directly responsible for 1.27 million deaths and contributed to an estimated 4.95 million fatalities worldwide, and without effective intervention the annual death toll is projected to reach 10 million by 2050, with economic losses exceeding US$3.4 trillion each year. A new critical narrative review, published in Biomedical Materials Science, takes a sobering look at the growing arsenal of non-antibiotic therapies proposed to fill the gap, and its central message is uncomfortable: most of these approaches are nowhere near the clinic, and none of them is likely to replace antibiotics outright.

The review, led by Karzan Qurbani and colleagues, systematically appraises nanoparticles, antimicrobial peptides, bacteriophages, probiotics and postbiotics, CRISPR-Cas gene tools, immune modulators, plant-derived bioactives and biomaterial-based platforms. The authors organize each strategy around a shared translational framework: mechanism of action and spectrum, therapeutic potential supported by in vivo or clinical evidence, and the barriers standing between laboratory promise and patient benefit. Their conclusion is that these technologies derive their value from diversifying antimicrobial mechanisms, enabling targeted interventions and reducing reliance on antibiotics, not from offering universal substitutes for conventional drugs.

The mechanistic logic is grounded in how bacteria actually resist treatment. Resistance arises through four principal routes: reduced drug uptake, active efflux, enzymatic drug inactivation and modification or protection of drug targets. Biofilms compound the problem, with their extracellular polymeric matrix acting as a diffusion barrier, sequestering antimicrobials, sheltering slow-growing persister cells and serving as hotspots for horizontal gene transfer. Nanoparticles, the review notes, can penetrate biofilms, degrade this matrix and disrupt structural integrity, exposing embedded bacteria to antimicrobial attack, while metal-based particles release ions that bind bacterial enzymes and interfere with DNA replication and repair.

Reactive oxygen species generation has emerged as a particularly attractive non-antibiotic mechanism. Unlike antibiotics that typically target single cellular pathways, ROS simultaneously attack membranes, proteins and genetic material through lipid peroxidation, protein oxidation and DNA strand breaks, making resistance through single genetic mutations extremely difficult. Piezocatalytic nanomaterials generate these radicals upon mechanical stimulation such as ultrasound. In one highlighted example, selenium-modified barium titanate nanoparticles achieved a 99.23 percent antibacterial rate against Staphylococcus aureus under ultrasound irradiation, promoted osteogenic differentiation and enhanced bone regeneration in an infected femoral bone-defect model, illustrating how antimicrobial and regenerative functions can be combined in a single externally activated platform.

Silver and zinc nanoparticles incorporated into porous titanium implants provided sustained ion release and antibacterial activity against methicillin-resistant S. aureus, while zinc-containing surfaces also enhanced pre-osteoblast metabolic activity. A quaternized chitosan derivative immobilized on titanium plates partially inhibited Staphylococcus epidermidis adhesion. Cationic antimicrobial polymeric nanoparticles delivered in an injectable Poloxamer 407 hydrogel achieved approximately 99 percent clearance of mature wound biofilm and promoted healing in a murine model. The design challenge, the authors stress, is balancing antimicrobial loading and controlled release against burst release, nanoparticle aggregation, leaching, loss of hydrogel integrity and cytotoxicity.

A handful of strategies have crossed into human testing, and their mixed results are instructive. The PhagoBurn study evaluated a GMP-produced Pseudomonas aeruginosa phage cocktail in a randomized phase I/II trial in patients with infected burn wounds; it demonstrated feasibility but failed to show sufficient efficacy at the administered phage concentration, underscoring the decisive roles of phage titer, bacterial susceptibility, formulation stability and dose optimization. Peceleganan, a topical antimicrobial peptide, was tested in a multicenter phase III trial of 570 patients with secondary skin-wound infections against silver sulfadiazine, reporting a higher clinical efficacy rate and no severe treatment-related adverse events, though the authors noted that bacterial clearance effectiveness remained uncertain. A randomized trial of 86 patients with infected wounds found greater bacterial clearance and wound healing with a topical silver nanoparticle formulation compared with mupirocin, but all participants also received concomitant therapies, so the findings support an antibiotic-sparing role rather than independent replacement.

Immune modulators tell a similar cautionary tale. Suvratoxumab, a monoclonal antibody targeting the S. aureus alpha-toxin, progressed to a phase II trial for prevention of ventilator-associated pneumonia; it was well tolerated, but the primary efficacy endpoint showed no statistically significant benefit. In the phase II SAATELLITE trial in mechanically ventilated patients colonized with S. aureus, the 5000-mg group showed a numerically lower incidence of pneumonia that did not reach significance. Meanwhile, recombinant human interferon-gamma has been evaluated in drug-susceptible and drug-resistant pulmonary tuberculosis, demonstrating feasibility of cytokine-based host-directed therapy, but the evidence remains disease- and pathogen-specific. Newer antibodies against pan-drug-resistant Klebsiella pneumoniae protected mice against bloodstream infection only when capsule-specific, showing that potent in vitro bactericidal activity does not predict in vivo protection.

Precision genetic tools face their own gauntlet. CRISPR-based antimicrobials can be programmed to kill resistant bacteria selectively, for instance by cutting the mecA resistance gene in S. aureus while sparing non-resistant strains and the surrounding microbiota, and a CRISPR-Cas3-enhanced phage cocktail, LBP-EC01, has entered a phase II study for uncomplicated E. coli urinary tract infection, where rapid reductions in urinary E. coli were observed in evaluable participants without definitive comparative efficacy evidence. Yet delivery of the large Cas protein-RNA complex across bacterial membranes remains difficult, bacteria can escape by mutating target sequences, off-target effects and biofilm barriers persist, and unresolved biosafety, dual-use and ecological concerns currently confine these systems to experimental or adjunctive contexts.

The review is equally blunt about the systemic obstacles. Regulatory frameworks at agencies such as the US Food and Drug Administration and the European Medicines Agency remain structured around chemically defined small molecules, creating classification problems for nanomaterials, peptides, phages and living therapeutics. Nanoparticle candidates face expanded safety requirements around long-term toxicity, biodistribution and environmental persistence, limiting most to localized or device-associated indications. Phage therapy lacks standardized regulatory pathways and is often evaluated case by case. Probiotics suffer from strain, dosage and formulation variability, with many products marketed as dietary supplements under less stringent quality control. Economic factors compound these barriers, particularly in low- and middle-income countries where the AMR burden is disproportionately concentrated.

Perhaps the review’s most important conceptual correction is its rejection of the resistance-proof label. Although multi-target mechanisms such as membrane disruption and ROS generation reduce the likelihood of single-step resistance, bacterial adaptive capacity remains substantial: stress-response activation, membrane remodeling, altered phage receptors, efflux modulation, genetic escape and biofilm adaptation all provide plausible evolutionary routes, and receptor mutation and CRISPR interference are already documented for phage and CRISPR systems. The authors argue that non-antibiotic strategies should be framed as adjunctive, context-dependent components of integrated antimicrobial stewardship and One Health frameworks, with future progress hinging on well-designed clinical trials, scalable and reproducible manufacturing, regulatory harmonization and equitable access, rather than on antimicrobial potency alone.

Subject of Research: Emerging non-antibiotic strategies against antimicrobial resistance and their translational limitations

Article Title: Antimicrobial resistance: emerging therapeutic alternatives and their translational limitations

Article References: Qurbani, K., Khdhr, R., Khdir, K., Hussein, S., Qadr, H. M., Saber, A. F., & Ali, S. (2026). Antimicrobial resistance: emerging therapeutic alternatives and their translational limitations. Biomedical Materials Science, 1(1), Article 8. https://doi.org/10.1186/s44495-026-00009-y

Image Credits: AI Generated

DOI: 10.1186/s44495-026-00009-y

Keywords: antimicrobial resistance, nanoparticles, antimicrobial peptides, phage therapy, CRISPR-Cas, probiotics, immune modulators, biomaterials, biofilms, clinical translation, One Health, Antimicrobial