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2 Wiadomości Chemiczne

2 2022

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Oddziaływanie przeciwdrobnoustrojowych peptydów z jonami metali : relacja między chemią koordynacyjną, strukturą, termodynamiką a sposobem działania

Dudek Dorota, Garstka Kinga, Miller Adriana, Dzień Emilia, Wątły Joanna, Hecel Aleksandra, Kozłowski Henryk, Rowińska-Żyrek Magdalena

Wiadomości Chemiczne

2022

[Z] 76, 5-6

365--391

Increasing bacterial and fungal drug resistance makes novel, effective antimicrobial treatments actively sought. Because of the general lack of resistance towards antimicrobial peptides (AMPs), they are being relied on as a novel class of therapeutics aimed to conquer drug-resistant bacteria and fungi. There are numerous ways in which AMPs might interact with pathogens, such as membrane disruption, production of reactive oxygen species, inhibition of cell wall, nucleic acid and protein synthesis or by the withdrawal of essential metal ions. Biologically indispensable metal ions, such as Zn(II) and Cu(II), which are the key players of this project, have a dual effect on the activity of antimicrobial peptides: (i) AMPs bind them, so that microbes cannot get enough metals essential for their life and virulence (withdrawal of metal ions, nutritional immunity) or (ii) AMPs need the given metal ion as a booster of their antimicrobial activity (metal ions affect the AMP charge and/or structure). In this chapter, we discuss the impact of the coordination of Cu(II) and Zn(II) to several antimicrobial peptides, focusing on the thermodynamics, structure and coordination chemistry. The comparison of these data to the outcome of biological growth studies (determination of minimal inhibitory concentration (MIC) of metalAMP complexes and their derivatives allows to draw conclusions about the relationship between the metal-antimicrobial peptide complex structure, stability mode of action and efficacy. In the nearest future, the most efficient complexes may serve as templates for a rational design of novel, more potent AMP-based therapeutics. Further improvement can be reached through the modification of the most promising AMP complexes using (i) specifically targeted antimicrobial peptides, in which the AMP will be covalently linked to a targeting peptide (Figure 1) or (ii) chimeric compounds comprising AMPs bound to conventional antimicrobials or peptidomimetic modifications (Figure 2).

Bakteryjne strategie wykorzystania jonów metali – kulisy chemii koordynacyjnej

Piasta Karolina, Mular Andrzej, Rola Anna, Dzyhovskyi Valentyn, Potok Paulina, Orzeł Bartosz, Potocki Sławomir, Stokowa-Sołtys Kamila, Kozłowski Henryk, Gumienna-Kontecka Elżbieta

Wiadomości Chemiczne

2022

[Z] 76, 5-6

287-308

In the Biological Inorganic Chemistry Group we are inspired to better understand metal ions acquisition and homeostasis in pathogenic bacteria, and in this review we present three different approaches to the role of these processes. The growing importance of a full understanding of the iron transport system in pathogens prompted us to study synthetic analogs of siderophores, used as structural probes in the process of iron uptake by microorganisms. The ferrichrome biomimetic analogs allowed efficient Fe(III) chelation under biological conditions and were recognized better by P. putida. than E. coli, suggesting differences in uptake mechanisms. Addition of a fluorescent probe to the compound allowed to track biological fate of studied complexes [1, 2]. Biomimetics of ferrioxamine E revealed their potential as radioactive 68Ga(III)-based probes [3], and studies of Zr(IV) complexes permitted to explain the in vivo behavior of desferrioxamine B as 89Zr(IV) radionuclide carrier [4], as well as design better chelators for this metal ion [5]. One of the possible mammalian immune system responsesto mycobacterial infection is the increase of Zn(II) concentration in phagosomes to a toxic level [6-8]. The mycobacterial SmtB protein is a transcription regulator that in the presence of high concentrations of metals, dissociates from DNA and activates the expression of metal efflux proteins. We focused on α5 Zn(II) binding domains of SmtB/BigR4 proteins [9], looking at the coordination modes and thermodynamics of their Zn(II) and Ni(II) complexes. The study points out the specificity of metal-ligand interactions and the effect of mutations on the coordination properties of studied systems. The project can be considered as an introduction to the new strategies in tuberculosis treatment based on Zn(II)/Ni(II)-sensitive mechanisms. F. nucleatum is an anaerobic bacteria present in the plaque. It leads not only to periodontal diseases but also, angina, purulent inflammation of the lung tissue or reproductive organs [10]. Moreover, F. nucleatum promotes colon cancer growth [11]. This bacteria strain promotes inflammation and tumorigenesis by modulating the tumor immune microenvironment [12, 13]. Microbial pathogens drive tumorigenesis in 15–20% of cancer cases [14]. However, not only microorganisms are considered a major risk factor, but also metal ions play an important role in tumor promotion [15, 16]. Therefore, our primary research goal is to investigate the effect of metal ions coordination on the activity of outer-membrane proteins from F. nucleatum and to answer whether these proteins increase the prooxidative activity of Cu(II) and Fe(II) ions [16-18].