Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2024

Synergy in action octapeptins potentiate repurposed drugs against antimicrobial resistance while mitigating toxicity   (#69)

Michelle Novais de Paula 1 , Johannes Zuegg 1 , Mark Blaskovich 1 , Alysha Elliott 1
  1. Institute for Molecular Bioscience (IMB), Brisbane, QLD, Australia

Antimicrobial resistance (AMR) poses a significant and rapidly evolving threat to human health, with alarming predictions suggesting that by the year 2050, it will be responsible for the loss of 10 million lives annually. This emphasises the urge for the development of novel therapeutic strategies.   

Among the therapeutic alternatives, lipopeptide antibiotics, such as FDA-approved polymyxins and the preclinical octapeptins, are membrane-targeting agents capable of treating infections caused by multi-drug-resistant pathogens. While polymyxins are already experiencing challenges with antimicrobial resistance, octapeptins show potential as a new avenue for combating AMR and are active against polymyxin-resistant strains. 

However, like polymyxins, octapeptins display nephrotoxicity which may limit their potential for human use. To address this challenge, it is crucial to find a balance between efficacy and toxicity.

Given their membrane-disrupting activity, the polymyxins have been explored for their potential to assist other compounds in entering, and killing, Gram-negative bacteria. In this study, we propose a screening approach to evaluate whether the octapeptins show similar synergistic potential when combined with drugs currently approved and available for use in other diseases.

Method: Synergistic activity was evaluated by calculating the fractional inhibitory concentration index (FICI). This value was obtained by testing the minimum inhibitory concentration of the compounds on their own and in combination with the octapeptins, with values ≤0.5 indicating a synergistic effect.

Results: The drugs that displayed higher hit rates in combination with the lipopeptides were Rifabutin, Rifaximin, and Sertraline (Table 1), which were particularly effective against Acinetobacter baumannii. The combinations showed enhanced activity through synergy, resulting in lower MIC values.

Conclusion: Leveraging the repurposing of already-approved drugs offers a practical strategy to overcome antimicrobial resistance. By systematically exploring combinations of repurposed drugs with modified octapeptins, we aim to uncover new avenues for combating antimicrobial resistance. This approach can not only enhance antimicrobial activity capable of overcoming resistant phenotypes but also potentially mitigate toxicity concerns by potentially reducing the required dosage of both antibiotics and potentiators thereby providing more effective and safer treatment options against multidrug-resistant infections.

 660214a19b049-Table_FICI.jpg

Table 1: Fractional Inhibitory Concentration Index(FICI). Hit was determined as FICI ≤0.5. Colour-coded by hit number.

 

 
  1. Adedeji, W. A. The Treasure Called Antibiotics. Ann Ib Postgrad Med 14, 56-57 (2016).
  2. Becker, B. et al. Synthesis of octapeptin C4 and biological profiling against NDM-1 and polymyxin-resistant bacteria. Bioorg Med Chem Lett 27, 2407-2409,j.bmcl.2017.04.027 (2017).
  3. Blaskovich, M. A. T., Pitt, M. E., Elliott, A. G. & Cooper, M. A. Can octapeptin antibiotics combat extensively drug-resistant (XDR) bacteria? Expert Rev Anti Infect Ther 16, 485-499, doi:10.1080/14787210.2018.1483240 (2018).
  4. Cheng, J. et al. Synergistic rifabutin and colistin reduce emergence of resistance when treating Acinetobacter baumannii. Antimicrob Agents Chemother 65, AAC.02204-20 (2021).
  5. Jim, O. N. Tackling drug-resistant infections globally: final report and recommendations. (Government of the United Kingdom, 2016).
  6. Meyers, E., Parker, W. L., Brown, W. E., Shoji, J. I. & Wakisaka, Y. A Nomenclature proposal for the octapeptin antibiotics. J. Antibiot. 29, 1241-1242, antibiotics.29.1241 (1976).
  7. Qian, C.-D. et al. Battacin (Octapeptin B5), a New Cyclic Lipopeptide Antibiotic from Paenibacillus tianmuensis Active against Multidrug-Resistant Gram-Negative Bacteria. Antimicrob Agents Chemother 56, 1458-1465, AAC.05580-11 (2012).
  8. Velkov, T. et al. Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria. Cell chemical biology 25, 380-391.e385, j.chembiol.2018.01.005 (2018).