Antimicrobial Peptides Derived from Xenorhabdus spp.: Untapped Troves of Novel Therapeutics
DOI:
https://doi.org/10.33687/ricosbiol.03.010.83Keywords:
Xenorhabdus, antimicrobial peptides (AMPs), non-ribosomal peptide synthetase (NRPS), RiPPs, lasso peptides, xenocoumacin, drug discovery, biosynthetic gene cluster (BGC)Abstract
The unending rise of antimicrobial resistance (AMR) is a serious threat to modern medicine. It makes infections that used to be treatable deadly and weakens the basis of surgical and cancer care. The discovery of novel antimicrobial classes with mechanistically distinct action is therefore a critical global health priority. Antimicrobial peptides (AMPs) represent a promising frontier in this endeavor, offering rapid, often non-specific mechanisms that challenge bacterial adaptation. The entomopathogenic bacteria of the genus Xenorhabdus have evolved into biochemical powerhouses, producing a staggering array of AMPs to survive within insect hosts while living in an obligate mutualism with Steinernema nematodes. This review provides a comprehensive analysis of the diverse classes of AMPs derived from Xenorhabdus, categorizing them into non-ribosomal peptides (NRPs) like the xenocoumacins and PAX peptides and ribosomally synthesized and post-translationally modified peptides (RiPPs) such as lasso peptides and novel bacteriocins. We delve deeply into their genetic basis, biosynthetic pathways, and multifaceted mechanisms of action, which range from membrane disruption and iron sequestration to intracellular targeting of essential processes. We further synthesize the evidence for their efficacy against multidrug-resistant ESKAPE pathogens, fungi, and protozoa, while critically evaluating the challenges of toxicity, stability, and scalable production. Finally, we present a forward-looking perspective on how advanced genomics, synthetic biology, and bioengineering strategies are poised to unlock the full potential of the Xenorhabdus pharmacopoeia, transforming these ecological weapons into a new generation of anti-infective agents.
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References
Bode, H. B. (2009). Entomopathogenic bacteria as a source of secondary metabolites. Current Opinion in Chemical Biology, 13 (2), 224–230. https://doi.org/10.1016/j.cbpa.2009.02.037
Bode, H. B., Guo, H., and Degenkolb, T. (2018). The future of natural product discovery: A paradigm shift from screening to genome mining. MedChemComm, 9 (1), 12–21. https://doi.org/10.1039/c7md00443j
Bozhüyük, K. A. J., Fleischhacker, F., Linck, A., Wesche, F., Tietze, A., Niesert, C. P., and Bode, H. B. (2019). De novo design and engineering of non-ribosomal peptide synthetases. Nature Chemistry, 11 (7), 653–661. https://doi.org/10.1038/s41557-019-0286-x
Brachmann, A. O., Reimer, D., Lorenzen, W., Augusto, E., and Bode, H. B. (2013). A novel type of iron chelator, the sturzins, produced by Xenorhabdus and Photorhabdus spp. Chemistry and Biology, 20 (7), 925–935. https://doi.org/10.1016/j.chembiol.2013.05.016
Cai, X., Nowak, S., Wesche, F., and Bode, H. B. (2017). The rhabdopeptide/xenortide family of peptides from the entomopathogenic bacterium Xenorhabdus is a complex class of novel antibiotics. Chemistry – A European Journal, 23 (58), 14585–14593. https://doi.org/10.1002/chem.201703342
Crawford, J. M., Portmann, C., Zhang, X., Roeffaers, M. B., and Clardy, J. (2021). Small molecule perimeter defense in entomopathogenic bacteria. Proceedings of the National Academy of Sciences, 109 (27), 10821–10826. https://doi.org/10.1073/pnas.1201160109
Kačar, D., Günter, T., and Bode, H. B. (2020). Lasso peptides: An intriguing class of bacterial natural products. ACS Chemical Biology, 15 (4), 968–978. https://doi.org/10.1021/acschembio.0c00084
Kuthning, A., Mosker, E., and Süssmuth, R. D. (2015). Engineering the heterologous expression of lasso peptides in E. coli by exploiting the xenolassin biosynthetic gene cluster. ACS Synthetic Biology, 4 (7), 817–825. https://doi.org/10.1021/sb500324n
Mahlapuu, M., Håkansson, J., Ringstad, L., and Björn, C. (2016). Antimicrobial peptides: An emerging category of therapeutic agents. Frontiers in Cellular and Infection Microbiology, 6 , 194. https://doi.org/10.3389/fcimb.2016.00194
Park, H. B., Lee, B., and Kim, Y. (2017). Anticancer activity of the entomopathogenic bacterium Xenorhabdus nematophila and its secondary metabolites. Journal of Microbiology and Biotechnology, 27 (4), 784–791. https://doi.org/10.4014/jmb.1612.12032
Reimer, D., Pos, K. M., Thines, M., Grün, P., and Bode, H. B. (2009). A natural prodrug activation mechanism in the biosynthesis of nonribosomal peptides. Nature Chemical Biology, 5 (7), 450–452. https://doi.org/10.1038/nchembio.167
Shi, Y., Li, Z., and Bode, H. B. (2022). The antimicrobial peptide xenocoumacin 1 inhibits bacterial ribosome assembly. Nature Communications, 13 (1), 535. https://doi.org/10.1038/s41467-022-28169-z
World Health Organization (WHO). (2021). Global action plan on antimicrobial resistance. Retrieved from https://www.who.int/publications/i/item/9789241509763
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