Bacterial resistance to registered antibiotics is one of the biggest challenges of mankind (Hernando-Amado et al., 2019; Murray et al., 2022) that begs for the discovery of novel antibacterial compounds. There are multiple examples of antibacterial agents that were repurposed as anticancer drugs [e.g., Methenamine (Altinoz et al., 2019)], or anticancer medications being repurposed as antibacterial ones, such as platinum(II) remedies. Indeed, cisplatin and carboplatin do have bacteriostatic properties on Acinetobacter, Mycobacteria, and Pseudomonas aeruginosa (Zhang et al., 2011; McCarron et al., 2012; Yuan et al., 2018) and other pathogens (Hummell and Kirienko, 2020). To complement the registered platinum-based anticancer agents, there is a thrust towards identifying novel complexes of transition metals with anticancer activity (Kenny and Marmion, 2019). Ruthenium complexes have emerged as anticancer agents, characterized by low toxicity (Melchart and Sadler, 2006; Mello-Andrade et al., 2018; Gano et al., 2019; Liu et al., 2019; Mihajlovic et al., 2020), good cellular entry properties (Graf and Lippard, 2012; Yadav et al., 2013) and with excellent targetability (Berger et al., 2008; Hanif et al., 2013; Florindo et al., 2014; Zeng et al., 2017; Kenny and Marmion, 2019; Hamala et al., 2020). In fact, a ruthenium complex, IT-139 has passed clinical phase I to be applied in colorectal cancer (Burris et al., 2016). Furthermore, rhodium (Leung et al., 2013; Gichumbi and Friedrich, 2018; Štarha and Trávníček, 2019; Máliková et al., 2021), osmium (Hartinger et al., 2011; Hanif et al., 2014; Gichumbi and Friedrich, 2018; Konkankit et al., 2018; Meier-Menches et al., 2018; Štarha and Trávníček, 2019; Nabiyeva et al., 2020; Li et al., 2021) and iridium (Leung et al., 2013; Liu and Sadler, 2014; Gichumbi and Friedrich, 2018; Konkankit et al., 2018; Štarha and Trávníček, 2019; Li et al., 2021) compounds were also described as anticancer agent candidates.

We synthesized a set of half-sandwich complexes of ruthenium(II), osmium(II), iridium(III) and rhodium(III) incorporating real C- and N-glycopyranosyl azole type N,N-bidentate ligands (Figure 1) (Kacsir et al., 2021; Kacsir et al., 2022). To get the 1,3,4-oxadiazole type L-1–L-3 ring-transformation of C-glycosyl tetrazoles I with picolinic acid was performed (Bokor et al., 2017), while for 1,2,3-triazole-based chelator L-4 copper(I) catalyzed azide alkyne cycloadditon (CuAAc) (Agrahari et al., 2021) of glucosyl azide II was used. The ligands were reacted with dimeric chloro-bridged platinum-group metal complexes in the presence of TlPF₆ to result in complexes Ru-1‒Ru-4, Os-1‒Os-4, Ir-1‒Ir-4 and Rh-1‒Rh-4 (Figures 1, 2). These complexes were identified to show cytostatic properties on carcinomas (representative data listed in Table 1), sarcomas and lymphomas in the low micromolar or submicromolar range, but have no bioactivity on primary, non-transformed fibroblasts (Kacsir et al., 2021; Kacsir et al., 2022). The compounds exert their cytostatic activity through inducing oxidative stress (Kacsir et al., 2021; Kacsir et al., 2022). The cytostatic activity of the compounds can be alleviated by vitamin E, an apolar, membrane antioxidant (Kacsir et al., 2021; Kacsir et al., 2022) suggesting that the compounds likely target the cell membrane or other apolar compartments in the cells. On the analogy of the bacteriotoxic activity of platinum or palladium compounds (Quirante et al., 2011; Vieites et al., 2011; Zhang et al., 2011; McCarron et al., 2012; Yuan et al., 2018; Hummell and Kirienko, 2020; Yufanyi et al., 2020; Frei et al., 2021; Mansour, 2021) we set out to assess whether the above cytostatic complexes Ru-1‒Ru-4, Os-1‒Os-4, Ir-1‒Ir-4 and Rh-1‒Rh-4 in Figure 2 (Kacsir et al., 2021; Kacsir et al., 2022), might have bacteriostatic properties. For comparative studies, the precursors of these complexes (Kacsir et al., 2021; Kacsir et al., 2022), such as the chloro-bridged platinum-metal dimeric complexes (Ru-dimer, Os-dimer, Ir-dimer and Rh-dimer) and the glycosyl heterocyclic N,N-bidentate ligands (L-1‒L-4), as well as, the reference platinum-based anticancer drugs (cisplatin, carboplatin, oxaliplatin) were also planned to be tested (Figure 2).

We assessed a set of half-sandwich type ruthenium(II), osmium(II), rhodium(III) and iridium(III) complexes of monosaccharide derivatives bearing bidentate N,N-chelating sets. The compounds discussed in the study and compounds with similar structure were identified earlier as anticancer agents (Florindo et al., 2014; Florindo et al., 2015; Florindo et al., 2016; Hamala et al., 2020; Kacsir et al., 2021; Kacsir et al., 2022). From the perspective of the current study it is important to note that the complexes were not active on primary human fibroblasts up to 33.3 µM (i.e., their IC₅₀ values were higher than 33.3 µM), but only had activity on neoplastic cell lines in low micromolar to submicromolar range (Kacsir et al., 2021; Kacsir et al., 2022) and here we show that these compounds have antimicrobial effects. These suggest that the complexes would be selective towards bacteria and neoplastic cells, which may be an advantageous feature in a clinical setting. The type of the central metal ion and the ligands, the stability and kinetic behavior as well as hydrolytic properties and the lipophilicity of a complex contribute significantly to its biological activity.

With respect to the central metal ion of the complex, osmium compounds were the most efficient on bacteria, followed by ruthenium complexes both in terms of the number of active complexes, as well as, their MIC values, while the iridium and rhodium complexes showed less activity. These findings are similar to our data on cancer cells (Kacsir et al., 2022). In other words, when comparing the Ru(II) and Os(II) complexes with hexahapto p-cymene ligand to the pentahapto arenyl-containing Ir(III) and Rh(III) complexes, the former ones were found to show better activity. There are multiple chemical features that can explain this finding. For the mentioned two pairs of metal ions in Ru and Os complexes, the hexahapto coordinated p-cym ligand provides less electron densitiy than the Cp* arenyl in the corresponding Rh or Ir compounds and their steric hindrance is different. Kinetic differences may also provide an explanation, as it is widely accepted that the half-sandwich type Os and Ir complexes, in general, exhibit much lower ligand exchange rates than the Ru and Rh analogues (Bruijnincx and Sadler, 2009). When comparing the IC₅₀ values for cancer cells with the MIC values against bacteria, it is apparent that the MIC values of the active complexes are higher than their IC₅₀ values on the most sensitive cancer cell model [e.g., for Os-4 IC₅₀ = 0.7 µM on 2780 ovarian cancer cells (Kacsir et al., 2021; Kacsir et al., 2022) vs. MIC range = 0.3–5 µM on multiresistant bacteria]. When comparing the MIC values of the complexes we found similar trends as a function of the central metal ion or the ligand as the IC₅₀ values of the complexes on cancer cells. Complexes of L-4 were considerably more effective than complexes of L-3, L-2 or L-1. These findings are also in good correlation with our observations on cancer cells (Kacsir et al., 2021; Kacsir et al., 2022) and may support the importance of the high hydrophobicity of the complexes. Importantly, for the complexes with good bacteriostatic activity (e.g., Os-4) there was no difference in the MIC value on the reference strains, the susceptible (MSSA, VSE) or the multiresistant isolates (MRSA, VRE). The activity of the complexes in previous antineoplastic studies was dependent on the apolar character of the compounds (Kacsir et al., 2021; Kacsir et al., 2022). We provided experimental evidence the carbohydrate moiety has a key role in bringing about the apolar character of the molecules by harboring multiple OBz groups. The replacement of the carbohydrate moiety with one single aromatic group largely hampered or eliminated the biological activity of the complexes (Kacsir et al., 2021). Therefore, the complexes supposedly affect the cell membrane that may be the case in bacteria as well. It is also of note that the exact target of the complexes has not been identified yet. Taken together, we identified osmium, ruthenium, iridium and rhodium complexes that exhibit antibacterial effects. The complexes have multiple advantageous properties, they are stable over extended periods [2 days were assessed in (Kacsir et al., 2021)], their MIC and IC₅₀ values are in the low micromolar or submicromolar range, respectively, and they are not active on non-transformed cells. As noted earlier, the active complexes have similar MIC values against multiresistant clinical isolates of MRSA and VRE and on sensitive isolates or reference strains suggesting a novel, yet unidentified target in Gram-positive bacteria that is not detoxified by existing resistance mechanisms. These findings suggest that the complexes studied here and similar ones may represent a novel class of antibiotics against multiresistant Gram-positive bacteria.