For decades, there has been a growing understanding of antibiotic overuse and the increasing prevalence of infections resistant to first-line treatment. The magnitude of this issue, now broadly recognized as antimicrobial resistance (AMR), is significant and continues to grow. In 2019, drug-resistant infections directly caused over 1.25 million deaths with a total associated drug-resistant deaths of 4.95 million (Piddock et al., 2024). Some projections suggest a potential rise to 10 million deaths within the next 25 years (Bayat et al., 2024). Simultaneously, the development of conventional antibiotics faces underfunding and a limited research pipeline (Piddock et al., 2024). An overview of antimicrobials is given in Figure 1.
Figure 1: Overview of Antimicrobials (sources: UK Health Security Agency)
Encouragingly, novel antimicrobial therapies are emerging from two compelling areas. The first bacteriophages, a relatively old field with therapeutic applications dating back over a century (Pirnay et al., 2024). The second involves utilizing advanced computational methods to explore microbiomes for antibacterial peptides (Santos-Júnior et al., 2024, Torres et al., 2024).
An interesting article, published in April this year, highlights the role of antibiotic usage in the evolution of pathogenic E. coli strains (Arredondo-Alonso et al., 2025). The authors sequenced thousands of bacterial genomes/plasmidomes from longitudinal samples of E. coli isolates in Norway. Their findings indicate that several plasmids play key roles in antibiotic resistance, competition, and virulence determinants. These determinants, as discussed by the authors, are important for understanding bacterial evolution (Arredondo-Alonso et al., 2025).
Bacteriophage Therapy Advances
As an undergraduate I found bacteriophages (that is viruses which specifically infect only bacteria) to be truly fascinating. Some early, elegant biochemistry and molecular biology of the bacteriophage world was essential to the establishment of genetic engineering tools taken for granted today. Something that might be less widely appreciated is their current and potential use in treating human bacterial infections.
While pioneering work in phage therapy dates back to 1919, it largely took a backseat with the widespread availability of antibiotics after World War II (Pirnay et al., 2024). However, the growing challenge of AMR is driving a resurgence of interest in bacteriophage therapy (BT). Despite this renewed attention, several key obstacles remain.
One significant challenge to use phages in the clinic is their highly targeted action (i.e., specific nature) (Bayat et al., 2024). This very-high fidelity is double-edged, both a benefit and a challenge. On one hand, it allows phages to selectively target or eliminate only a very specific (presumably only the pathogen) species and leaves others unaffected thus reducing unwanted side effects. On the other hand, this high specificity means that that phage therapy is essentially personalized medicine and as such often requires time consuming and costly screening of phage libraries to find the right match for a particular infection. This connects to the second roadblock: the absence of universal phage libraries for screening. Currently, these resources are often maintained within local, national or military research laboratories (Bayat et al., 2024).
I came across an interesting recent report by Pirnay and team (2024) from a Belgian consortium detailing the outcomes of personalized BT in 100 patients between 2008 and 2022. These patients with difficult-to-treat infection in respiratory tract, skin, soft tissue, or bone experienced clinical improvement 77% of the time. The BT therapy involved the use of 26 individually selected bacteriophages and 6 different bacteriophage cocktails. In some cases, the individual bacteriophages were pre-adapted to specifically target and lyse the bacterial strains identified from the relevant patient. Notably, the combination of BT with conventional antibiotic therapy appeared to be particularly effective in clearing the infections. Furthermore, the study reported no serious adverse events associated with the BT. While acknowledging the study’s limited size and scope, the findings suggest the significant potential of applied BT, even within existing constraints (Pirnay et al., 2024).
A recent report (Bayat et al., 2024) details the development of high-throughput screening platform aimed at addressing some of the obstacles hindering the wider adoption of personalized BT. Instead of the more standard bacterial lawn/phage plaque test the group introduced an alternative phage library encapsulated and stabilized with assay reagents in shelf-stable tablets. These tablets are organized in 96-well plates to enable rapid high-throughput screening. Each tablet encapsulates a single phage along with luciferin/luciferase reagents stabilized in a sugar matrix. This design allows rapid detection of ATP release resulting from bacterial lysis through bioluminescence. The authors successfully screened randomly selected multi-drug resistant clinical isolates of Pseudomonas aeruginosa in their multi-well plate system, observing phage activity within 30 to 90 minutes. Similar detection capabilities were also demonstrated with isolated strains of Escherichia coli, Salmonella enterica and Staphylococcus aureus (Bayat et al., 2024). These findings suggest that while BT is currently underutilized, its potential for future applications could be significantly enhanced by minimizing existing limitations.
The Promising Class of Antimicrobial Peptides (AMPs)
Recent advancements in metagenomics have enabled researchers to explore microbiome databases for potential antimicrobial macromolecules. In the summer of 2024, two groups published studies in this area (Santos-Júnior et al., 2024, Torres et al., 2024).
A very promising class of these molecules are antimicrobial peptides (AMPs). These are defined as peptides 10 to 100 amino acids in length that can inhibit microbial growth (Santos-Júnior et al., 2024). They are naturally produced by a wide variety of both unicellular and multicellular organisms including metazoans (Torres et al., 2024). Naturally occurring AMPs can be synthesized through various biological processes, including proteolysis, non-ribosomal protein assembly or by gene-encoded ribosomal synthesis. These peptides are believed to be part of ancient “host defense” mechanisms and are also produced by bacteria as a means of competition within ecosystems such the human gut (Arredondo-Alonso et al., 2025).
The study by Torres et al. (2024) involved a computational screening of over 440,000 small open reading frame (smORF) encoded proteins, specifically peptides shorter than 50 residues, obtained from 1773 metagenomes across four body sites of 263 subjects. From this screen they identified 323 candidate smORF-encoded peptide antibiotics (SEPs). Subsequently, 78 of these candidates were synthesized and tested for antimicrobial activity against 11 clinically relevant pathogenic bacteria. Notably, 70% of the tested SEPs demonstrated antimicrobial properties. Leading candidates from the pathogen screen were further tested in vivo using two different mouse models to assess their efficacy in treating skin and deep tissue infections. The lead candidate prevotellin-2, isolated from Prevotella copri, exhibited comparable activity to the established gold standard antibiotic polymyxin B in the in vivo models.
In an even broader scope effort, Santos-Júnior et al. (2024) screened an impressive 63,000 metagenomes and 87,000 high-quality bacterial and archaea microbiomes, identifying over 850,000 candidate AMPs collectively referred to as AMPSphere. From this large pool, 100 of the candidates were synthesized and 63 exhibited activity in vitro against at least one of the 11 clinically relevant pathogenic strains known as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species). The most promising candidates were then evaluated in a mouse model for skin infection. Four of these peptides showed in vivo activity, although they were slightly less potent than polymyxin B. Taken together, these two studies highlight the exciting possibility of discovering hundreds, if not thousands, of clinically effective AMPs.
Companies with Interesting Phage Therapy or AMP Programs
Phage Therapeutics
Locus Biosciences has developed LBP-EC01, a bacteriophage therapy cocktail designed for the treatment of urinary tract infections and other infections caused by E. coli. This innovative cocktail, LBP-EC01, is engineered with a CRISPR-Cas3 construct. This allows it to target the E. coli genome, leveraging both the natural lytic properties of the bacteriophage and the DNA-targeting activity of CRISPR-Cas3. Currently, LBP-ECO1 is in phase II clinical trial specifically for urinary tract infections (UTIs) caused by antimicrobial-resistant and multi-drug-resistant E. coli. Early results from the trial, which centered on defining treatment regimens, still noted rapid and durable reduction of E. coli, with corresponding elimination of clinical symptoms (Kim et al. 2024).
BiomX, an Israel-based microbiome therapeutics company, is developing therapeutics using phage therapies. Their goal is to eradicate harmful bacteria that contribute to chronic diseases. BiomX has a few key programs in their pipeline. BX0004 is a bacteriophage therapy currently in development for Cystic Fibrosis patients who have chronic Pseudomonas aeruginosa infection (NCT05010577). Additionally, they are developing BX211, a phage therapy aimed at treating diabetic complications linked to Staphylococcus aureus infections. While there haven’t been any published results for BX211 yet, the company announced positive preliminary results from their Phase II clinical trials (DANCE™), earlier this year.
Eligobiotics, a company headquartered in Paris, France, focuses on developing antibiotics for microbiome and bacteria-associated diseases. Researchers from Eligobiotics recently published an article in Nature (Brödel et al., 2024) demonstrating their innovative approach to modifying E. coli within the mouse gut using a phage-derived vector. Their study demonstrated the effectiveness of a modified phage lambda carrying resistance genes both in living organisms (in vivo) and in lab settings (in vitro). This research highlights the potential of directly modifying bacteria in the gut, suggesting a novel therapeutic pathway for human diseases (Brödel et al., 2024)
AMP Therapeutics
Jiangsu ProteLight Pharmaceutical & Biotechnology has developed Peceleganan (PL-5), an antimicrobial peptide for treating of wound infections. They recently completed a Phase III clinical trial for PL-5 in China in 2024. This trial investigated a topical spray formulation of PL-5 for the treatment of skin wound infections. The reported results from this study indicated that the Peceleganan spray was not only safe but also demonstrated greater effectiveness compared to the standard treatment of 1% silver sulfadiazine.
Nanopharmaceutics is a clinical-stage specialty pharmaceutical company focused on creating treatments for cancer, central nervous system disorders, and infectious diseases. Their development pipeline includes Ramoplanin, a glycolipodepsipeptide antibiotic. This compounds has demonstrated activity against a range of challenging pathogens, such as C. difficile, vancomycin-resistant Enteroccocus, and methicillin-resistant Staphylococcus aureus. Notably, Ramoplanin functions by inhibiting cell wall peptidoglycan biosynthesis.
SetLance, an Italian biotech company focused on creating branched peptide-based drug candidates to treat serious bacterial infections and cancer. Their product SET-M33, is an optimized version of an artificial peptide sequence isolated from a peptide library. SET-M33 has demonstrated activity against a range of Gram-negative bacteria, including clinical isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumanii, and other Enterobacteriaceae. A unique aspect of SET-M33 is its synthesis using D-isomer amino acids, which makes it resistant to degradation by proteases.
TAXIS Pharmaceuticals, a privately held company located in New Jersey, focuses on developing compounds to combat the increasing challenge of antimicrobial resistance (AMR). One of their lead molecules in development is TXA709, a small molecule that inhibits the bacterial FtsZ protein. As FtsZ is essential for bacterial cell division, its inhibition represents a promising approach. In addition, TAXIS is also pursuing the development of inhibitors targeting bacterial efflux pumps and bacterial dihydrofolate reductase as innovative strategies to overcome current AMR mechanisms.
References
Arredondo-Alonso et al., Plasmid-driven strategies for clone success in Escherichia coli. (2025) Nat Commun, Apr 3;16(1):2921.
Bayat et al., High throughput platform technology for rapid target identification in personalized phage therapy. (2024) Nat Commun, Jul 11;15(1):5626.
Brödel et al., In situ targeted base editing of bacteria in the mouse gut. (2024) Nature, Aug;632(8026):877-884.
Kim et al., Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial. (2024) Lancet Infect Dis, Dec;24(12):1319-1332.
Piddock et al., Advancing global antibiotic research, development and access. (2024) Nat Med, Sep;30(9):2432-2443.
Pirnay et al., Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study. (2024) Nat Microbiol, Jun;9(6):1434-1453.
Santos-Júnior et al., Discovery of antimicrobial peptides in the global microbiome with machine learning. (2024) Cell, Jul 11;187(14):3761-3778.e16.
Torres et al., Mining human microbiomes reveals an untapped source of peptide antibiotics (2024) Cell, Sep 19;187(19):5453-5467.e15.
