Beyond Antibiotics: The Expanding Role of Anti-Infective APIs in Bacterial Infection

As antibiotic resistance becomes more of a challenge in the treatment of bacterial infections, and fewer new antibiotics are coming through the research pipeline, the biopharma industry is having to work hard to find alternative approaches. A piece published in May 2024 in Pharma Sources Industry Insights on The ongoing AMR challenge covered antibiotics, antibodies, bacteriophages and vaccines. This follow-up article focuses on alternatives to antibiotics, including antimicrobial peptides, faecal-based products, nanoparticles, pre-, pro-, post- and synbiotics, and other approaches. [1]

Creating an alternative: Antimicrobial peptides

Antimicrobial peptides (AMPs), first isolated from a soil Bacillus strain in 1939, have activity against viruses, bacteria, fungi and parasites. They may be synthetic or from natural sources, including bacteria, protozoa, fungi, plants, insects and animals. The antibacterial AMPs mostly act by targeting bacterial cell membranes and disintegrating the lipid bilayer. Others pass through the membrane and inhibit cell pathways, including DNA replication and protein synthesis. AMPs have potential in controlling biofilms and dealing with dormant persister cells, and bacteria appear to be less likely to develop complete resistance to AMPs. [2-4]

Examples of AMPs in development include:

· NovaBiotics is developing NP213 (Novexatin), which is based on the natural peptides found in nails and skin. This is in clinical trials for the treatment of nail disorders. [5]

· Soligenix is developing dusquetide (SGX943), an innate defence regulator (IDR). This acts by modulating the immune response rather than targeting the bacterium itself, which may reduce the risk of resistance. Dusquetide is in clinical trials for the treatment of antibiotic-resistant infections and may be used in combination with antibiotics. [6]

· The proteasome, which breaks down proteins in the cell, creates proteasome-derived defence peptides. In a mouse study, proteasome-derived defence peptides destroyed bacteria and improved survival rates in mouse models of pneumonia and sepsis. They could have potential as therapeutics in infectious disease. [7]

Using the body’s own bacteria: Faecal microbiota transplants

The use of faecal microbiota transplants (FMT) from a healthy donor to the gastrointestinal (GI) tract of someone with a GI disorder goes back to fourth century China when a suspension of human faeces was used to treat food poisoning and severe diarrhoea. The approach re-emerged in 1958 when rectal administration of donor faeces was used to treat four patients with pseudomembranous colitis, and again in 2008 during a Clostridioides difficile (previously known as Clostridium difficile) infection pandemic. [2]

In FMT, a suspension of commensal bacteria-containing faeces from a health donor is administered intestinally via a colonoscopy or enema, or using a nasogastric or nasoduodenal tube. It has proven effective in treating and preventing C difficile infection (CDI) following antibiotic treatment in adults, and in reinstating gut microbial diversity and functionality. [2]

In 2023, The FDA approved the first orally administered faecal microbiota product for the prevention of recurrence of C difficile infection. Known as Vowst (SER-109), the capsule was developed by Seres Therapeutics. [8] Seres Therapeutics is also developing SER-155, a biotherapeutic made up of a mixture of commensal bacteria, and has carried out a Phase Ib study. SER-155 has been designed to decolonize GI pathogens, improve epithelial barrier integrity, and induce immune tolerance to prevent bacterial bloodstream and AMR infections as well as other pathogen-associated negative clinical outcomes in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. [9]

Using nanoparticles to attack bacteria

Nanoparticles are small particles between 1 nm and 100 nm. Metal-based nanoparticles have inherent antimicrobial properties. Silver-, copper- and zinc oxide-based nanoparticles are used in wound dressings and as antimicrobial coatings on medical devices and in healthcare settings. Polymer-based nanoparticles can be used to deliver antibiotics and other antimicrobials directly to sites of infection. Combining metal and polymers, two different metals, or lipids and polymers in composite nanoparticles can enhance antimicrobial activity. There may be issues associated with using nanoparticles, including manufacturing challenges and potential toxicity. [2, 10]

Researchers at Oxford University are developing an ultrasound-activated nanoscale drug delivery platform (nanodroplets). When loaded with four different antimicrobial agents and activated by ultrasound, the nanodroplets reduced the antibiotic concentration required to prevent the growth of clinical bacterial strains and biofilms. [11]

Pitting microbiota against infection: Prebiotics, probiotics, postbiotics and synbiotics

Prebiotics are mixtures of insoluble carbohydrates, and these have been shown to modulate gut microbiota and have potential to improve immune function. [12]

Probiotics (mixtures of live organisms) are widely available in shops and online as functional foods and dietary supplements. Studies show specific combinations of probiotic organisms have potential in combination with eradication therapy in Helicobacter pylori infection, as well as in reducing urinary tract infection episodes in women, preventing ventilator-associated pneumonia and preventing or curing infections of ESKAPE pathogens. [2, 13]

Postbiotics (the bioactive compounds made when probiotics break down prebiotics) and synbiotics (mixtures of probiotics and prebiotics) have been shown to reduce disease-causing bacteria in animal studies [8]

Other approaches in early research 

Toxin-antitoxin (TA) systems are typically pairs of genes in bacterial genomes that encode a toxic protein and an antitoxin, and under normal circumstances the two remain in balance. If the antitoxin is degraded, the toxin is released producing a bactericidal or bacteriostatic effect. Modulating the toxins and antitoxins could have potential to treat bacterial infections, but the large variety of TA systems across bacterial strains could limit its practicality. [2]

Peptide nucleic acids (PNAs) are synthetic molecules with antibacterial efficacy that have potential to be tailored to inhibit bacterial growth or increasing the susceptibility to conventional antibiotics. [14]

Immunotherapeutics such as cytokines and immune checkpoint inhibitors have been assessed but the success levels have only been moderate. [13]

Photodynamic therapies, using non-toxic photosensitisers and light, can be used to destroy bacteria with little or no selective pressure for resistance development. They are limited to surface use but have potential in infected wounds and skin ulcers. [15]

Moving forward against AMR

As the impact of antibiotic resistance continues to grow, driven by climate change, urban development and socioeconomic factors, and antibiotic consumption in healthcare and agriculture, there is an urgent need for therapeutics that can be used alone or in combination with antibiotics. [16] 

References 

1.Elvidge, S., The ongoing AMR challenge. Pharma Sources, 6 May 2024. Available from: https://www.pharmasources.com/industryinsights/the-ongoing-amr-challenge-76380.html.

2.Yarahmadi, A., et al., Beyond antibiotics: exploring multifaceted approaches to combat bacterial resistance in the modern era: a comprehensive review. Front Cell Infect Microbiol, 2025. 15: p. 1493915.

3.Cresti, L., G. Cappello, and A. Pini, Antimicrobial Peptides towards Clinical Application-A Long History to Be Concluded. Int J Mol Sci, 2024. 25(9).

4.Bahar, A.A. and D. Ren, Antimicrobial peptides. Pharmaceuticals (Basel), 2013. 6(12): p. 1543-75.

5.NP213 (Novexatin). NovaBiotics. Last accessed: 27 May 2025. Available from: https://novabiotics.co.uk/np213/.

6.SGX943 for Bacterial Infection Treatment. Soligenix. Last accessed: 27 May 2025. Available from: https://www.soligenix.com/pipeline-programs/sgx943-for-infectious-disease/.

7.Goldberg, K., et al., Cell-autonomous innate immunity by proteasome-derived defence peptides. Nature, 2025. 639(8056): p. 1032-1041.

8.FDA Approves First Orally Administered Fecal Microbiota Product for the Prevention of Recurrence of Clostridioides difficile Infection. US Food and Drug Administration. Last accessed: 26 April 2023. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides.

9.Our programs. Seres Therapeutics. Last accessed: 27 May 2025. Available from: https://www.serestherapeutics.com/our-programs/.

10.Mondal, S.K., et al., Antimicrobial nanoparticles: current landscape and future challenges. RSC Pharm, 2024. 1: p. 388-402.

11.Choi, V., D. Carugo, and E. Stride, Repurposing antimicrobials with ultrasound-triggered nanoscale systems for targeted biofilm drug delivery. NPJ Antimicrob Resist, 2025. 3(1): p. 22.

12.Al-Habsi, N., et al., Health Benefits of Prebiotics, Probiotics, Synbiotics, and Postbiotics. Nutrients, 2024. 16(22).

13.Mishra, S.K., et al., Harnessing Non-Antibiotic Strategies to Counter Multidrug-Resistant Clinical Pathogens with Special Reference to Antimicrobial Peptides and Their Coatings. Antibiotics, 2025. 14(1): p. 57.

14.El-Fateh, M., A. Chatterjee, and X. Zhao, A systematic review of peptide nucleic acids (PNAs) with antibacterial activities: Efficacy, potential and challenges. Int J Antimicrob Agents, 2024. 63(3): p. 107083.

15.Cardozo, A.P.M., et al., Antimicrobial photodynamic therapy with methylene blue and its derivatives in animal studies: Systematic review. Photodermatol Photoimmunol Photomed, 2024. 40(4): p. e12978.

16.Wang, Y., et al., A global atlas and drivers of antimicrobial resistance in Salmonella during 1900-2023. Nat Commun, 2025. 16(1): p. 4611.