Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria

Abstract

Vancomycin is known to bind to Zn(II) and can induce a zinc starvation response in bacteria. Here we identify a novel polymerization of vancomycin dimers by structural analysis of vancomycin-Zn(II) crystals and fibre X-ray diffraction. Bioassays indicate that this structure is associated with an increased antibiotic activity against bacterial strains possessing high level vancomycin resistance mediated by the reprogramming of peptidoglycan biosynthesis to use precursors terminating in D-Ala-D-Lac in place of D-Ala-D-Ala. Polymerization occurs via interaction of Zn(II) with the N-terminal methylleucine group of vancomycin, and we show that the activity of other glycopeptide antibiotics with this feature can also be similarly augmented by Zn(II). Construction and analysis of a model strain predominantly using D-Ala-D-Lac precursors for peptidoglycan biosynthesis during normal growth supports the hypothesis that Zn(II) mediated vancomycin polymerization enhances the binding affinity towards these precursors.

Bacillus subtilis Regulators MntR and Zur Participate in Redox Cycling, Antibiotic Sensitivity, and Cell Wall Plasticity

“…Third, there is an intimate connection between metal ions and antibiotic activity Some antibiotics are known to require metal ions for their activity (69). When not required to mediate target binding, interaction of metal ions with antibiotics can provide an additional mode of antibacterial action, as seen, for example, with Zn 2ϩ , which potentiates the antibiotic activity of vancomycin (70), and with ZnMgO, which increases ciprofloxacin activity (71). We showed here that ΔmntR and Δzur cells accumulate some metal ions (Table 5), which may potentiate antibiotic activity.…”

Chemotranscriptomic Profiling Defines Drug-Specific Signatures of the Glycopeptide Antibiotics Dalbavancin, Vancomycin and Chlorobiphenyl-Vancomycin in a VanB-Type-Resistant Streptomycete

“…The response of the sigE regulon to dalbavancin was also highly similar, but slightly less well conserved. In contrast, induction of a transcriptional response associated with zinc starvation stress through physicochemical interaction of vancomycin with Zn 2+ ( Zarkan et al, 2016 , 2017 ) is largely absent in dalbavancin treated cultures and is attenuated in the response to chlorobiphenyl-vancomycin ( Figure 3C ).…”

“…Vancomycin, chlorobiphenyl-vancomycin and dalbavancin induce distinct transcriptional responses in the VanB-type resistant streptomycete S. coelicolor, despite sharing the same primary mode of antibiotic action and a high degree of chemical similarity. Vancomycin molecules bind Zn 2+ ions via interaction with nitrogen and oxygen atoms in the N-terminal methylleucine moiety, a phenomenon initially observed due to the identification of a strong zinc-starvation response by exposure to vancomycin in S. coelicolor (Zarkan et al, 2016(Zarkan et al, , 2017. The absence of a zinc-starvation response following dalbavancin treatment ( Figure 3C) correlates with the absence of this methylleucine group in the structure of FIGURE 5 | Heatmap summarising the transcripts changing significantly in response to two or more of the glycopeptide antibiotics used relative to the control treatment.…”

Exploring multiple effects of Zn0.15Mg0.85O nanoparticles on Bacillus subtilis and macrophages

“…The increased permeability of bacterial cell membrane facilitates ciprofloxacin uptake, which is expected to enhance its efficiency. Nevertheless, metal oxide NPs as well as divalent metal ions were reported to complex antibiotics and improve their antibacterial affinity 45 – 47 . For instance, protonated nitrogen atoms of ciprofloxacin quinolone ring may directly bind hydroxylated Zn 0.15 Mg 0.85 O NPs by ionic bonds as evidenced for some divalent metal ions by spectroscopic and X-ray analyses 48 .…”