Poster Presentation 21st International Conference on Biological Inorganic Chemistry 2025

Understanding bacterial metal transport to tackle antibiotic resistance (#434)

Aleksandra Hecel 1 , Arian Kola 2 , Daniela Valensin 2 , Danuta Witkowska 3 , Henryk Kozlowski 1 3 , Magdalena Rowinska-Zyrek 1
  1. Faculty of Chemistry, University of Wroclaw, Wroclaw, Poland
  2. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
  3. Institute of Health Sciences, University of Opole, Opole, Poland

There is a significant gap in understanding bacterial metal transport systems, which are more diverse than in eukaryotes. Some metal uptake mechanisms are species-specific, adding complexity to their study. Differences in metal transport between bacterial pathogens and their hosts represent key targets for antimicrobial strategies. Exploring bacterial metal transport is crucial for designing novel therapies, especially in the context of rising antibiotic resistance.1

To study bacterial peptide metal transporters, we employed potentiometric titrations, isothermal titration calorimetry (ITC), and advanced spectroscopic techniques (UV-Vis, CD, EPR, NMR), alongside mass spectrometry (MS), enabling detailed characterization of metal binding and transport mechanisms.

Zinc uptake in bacteria is regulated through systems like ZnuABCD. Histidine-rich loops in ZnuA and ZnuD proteins capture Zn(II), acting as ‘fishing nets’ for metal transfer. ZnuD-Cu(II) binding induces a conformational shift to a polyproline II-like helix, enhancing our understanding of bacterial zinc acquisition.2,3 Nickel acquisition is particularly challenging for pathogens due to its toxicity. The nickel chaperone HypB, involved in [NiFe]-hydrogenase maturation, shows high-affinity Ni(II) binding at its N-terminal site, offering new insights into nickel homeostasis.4 Despite limited studies on copper transport, recent work on OprC, an outer membrane transporter, has provided insights into bacterial copper acquisition. OprC binds copper via a unique CxxxM-HxM metal-binding site, and its interaction with the metallophore CopM revealed that the MxxHH motif in CopM strongly binds Cu(II) ions. This suggests that the CopM MxxHH domain binds Cu(II) very strongly and may be unable to release it to the OprC, implying that it is transported together with copper ions through OprC into the bacterial cell.5

These findings offer critical insights into bacterial metal transport, laying the groundwork for future in vivo studies. By targeting these pathways—especially through strategies like the "Trojan horse," where antibiotics are attached to bacterial peptide metallophores for specific transporter recognition—we can develop innovative therapies that combat the growing threat of antibiotic resistance.

 

Acknowledgments: The work was supported by the National Science Centre (Grant UMO-2023/51/D/ST5/01798), by the Polish National Agency for Academic Exchange (Grant BPN/BKK/2022/1/00005) and Excellence Initiative – Research University Grant BPIDUB.13.2024.

  1. Kozlowski, H.; Piasta, K.; Hecel, A.; Rowinska-Zyrek, M.; Gumienna-Kontecka, E. Metallophores: How do human pathogens withdraw metal ions from the colonized host, Elsevier 2023.
  2. Hecel, A.; Kola, A.; Valensin, D.; Kozlowski, H.; Rowinska-Zyrek, M. Inorg. Chem. 2020, 59, 1947-1958.
  3. Hecel, A.; Rowinska-Zyrek, M.; Kozlowski, H. Inorg. Chem., 2019, 58, 5932-5942.
  4. Hecel, A.; Kola, A.; Valensin, D.; Kozlowski, H.; Rowinska-Zyrek, M. Dalton Trans. 2021, 50, 12635-12647.
  5. Hecel, A.; Kola, A.; Valensin, D.; Witkowska, D. Inorg. Chem. 2025, 64, 6, 2936–2950.