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Non-traditional Approaches to Antimicrobial Therapies

15 Feb 22

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Antimicrobial resistance (AMR) continues to be a growing concern and antimicrobials currently available continue to become less effective leading to more persistent and sometimes untreatable infections. In Europe alone, antibiotic resistant infections are reported to result in approximately 33,000 deaths annually (Paulin, Alm, and Beyer 2020).

Of the recently approved antibiotics, 80% (9/11) are derivatives of existing antibiotic classes and have limited but important clinical benefits over existing treatment. The World Health Organization (WHO) reveals that none of these newly approved agents, nor any of the traditional antibiotics currently in clinical development, sufficiently fully address the problem of drug resistance. An exception is cefiderocol which is active against all three WHO critical Gram-negative pathogens (Carbapenem-resistant Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa) and inhibits a variety of β-lactamases, including AmpC, extended-spectrum β-lactamases, and, importantly, both serine-carbapenemases (KPC and OXA) and metallo-β-lactamases (WHO 2021).

An alternate approach to traditional antibiotics is to develop non-traditional agents which are defined as: “Antimicrobial therapeutics that work through other means i.e., not a small molecule and/or utilises a non-traditional target” (Rex et al. 2019). These novel agents are diverse in action including agents that modify the microbiome, chelate metals needed for bacterial enzyme activity, nucleic acids that interfere with bacterial DNA, antibodies and bacteriophages that target specific pathogens, and anti-virulence agents (Rex et al. 2019).

A large number of the non-traditional pre-clinical pipeline projects are focused on a single pathogen species, a distinct shift away from the broad-spectrum antibiotic concept held for many years. According to the WHO (WHO 2021), of the 70 antibacterial agents in clinical development in 2020, 27 were non-traditional antibacterial agents (9 antibodies, 4 bacteriophages and phage-derived enzymes, 8 microbiome-modulating agents, 2 immunomodulating agents, and 4 miscellaneous agents).

Whilst many non-traditional agents in development are antimicrobial, others have no inherent effect on bacterial growth in vitro. Anti-virulence agents are an example, and these agents aim to inhibit the production or activity of virulence factors (VFs) thereby avoiding or alleviating infection. VFs currently in pre-clinical development include toxins, adhesins, quorum sensing agents, and siderophores, amongst others (WHO 2021).

A recent example of an approved non-traditional agent is the human monoclonal antibody (MAb), Bezlotoxumab, which binds to the Clostridioides difficile toxin B and is indicated to prevent recurrent C. difficile infection in at-risk adults (Theuretzbacher and Piddock 2019). Other MAbs in development target bacterial surface epitopes and are hypothesised to increase bacterial clearance through enhancing antibody dependent phagocytosis and/or complement-mediated bactericidal activity (WHO 2021).

Modifying and engineering the human microbiome is another attractive option to prevent and resolve infection. In 2019 alone, more than 10 small pharmaceutical companies were developing microbiome therapies for infectious diseases, using carefully selected cocktails of bacteria or bacterial spores containing the “active components” of the complex microbiota (Theuretzbacher and Piddock 2019). This approach assumes that rebuilding the microbiome after an infection or preserving the microbiome to prevent re-infection will then translate into clinical benefits.

Phage therapy has the potential to treat individual bacterial infections or to be used in combination with other antibacterial and antibiotic treatments. Phages have the ability to amplify at the site of infection and to cause death and lysis of their bacterial targets as well as potentially being used as specific nano-delivery vehicles (Theuretzbacher and Piddock 2019). This is an attractive approach because phages can specifically eliminate an infectious bacterial species without affecting the host microbiota. Clinical trials with intravenous phage therapy are now underway and time will tell whether this approach can help solve the global emergency of antimicrobial resistant infections (Raza et al. 2021).

Nanotechnology is also being explored to either better deliver antimicrobial agents to the site of infection or as antimicrobial substances themselves (Raza et al. 2021). As these nanoparticles are synthesised, and bacteria will not have been exposed to them before, it is assumed that these molecules will evade resistance mechanisms. Cell penetrating approaches, such as cell-penetrating peptides, appear to act as low-toxicity carriers, delivering agents such as antisense oligonucleotides to infected areas and across bacterial cell walls more effectively (Chen et al. 2021).


In conclusion, many novel attempts to solve AMR are being researched. This is even more important in today’s world where the COVID-19 pandemic has forced the additional use of antibiotics to treat secondary infections which leads to an increased pressure for resistance selection. As established traditional antibiotics continue to lose their effectiveness, the search for non-traditional approaches may help to alleviate a looming global disaster.


  1. Chen, H., D. Battalapalli, M. S. Draz, P. Zhang, and Z. Ruan. 2021. ‘The application of cell-penetrating-peptides in antibacterial agents’, Curr Med Chem.
  2. Paulin, Sarah, Richard A. Alm, and Peter Beyer. 2020. ‘A novel pre-clinical antibacterial pipeline database’, PLoS One, 15: e0236604.
  3. Raza, S., K. Matula, S. Karon, and J. Paczesny. 2021. ‘Resistance and Adaptation of Bacteria to Non-Antibiotic Antibacterial Agents: Physical Stressors, Nanoparticles, and Bacteriophages’, Antibiotics (Basel), 10.
  4. Rex, John H., Holly Fernandez Lynch, I. Glenn Cohen, Jonathan J. Darrow, and Kevin Outterson. 2019. ‘Designing development programs for non-traditional antibacterial agents’, Nature Communications, 10.
  5. Theuretzbacher, U., and L. J. V. Piddock. 2019. ‘Non-traditional Antibacterial Therapeutic Options and Challenges’, Cell Host Microbe, 26: 61-72.
  6. WHO. 2021. ‘2020 Antibacterial agents in clinical and preclinical development: an overview and analysis’.

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