Occurrence of vanHAX and Related Genes beyond the Actinobacteria Phylum

Abstract

Clinically relevant glycopeptide antibiotics remain among the most successful classes of natural antibacterials. This success, however, is endangered by the spread of glycopeptide resistance genes, also known as van genes. Thus, it is important to trace and comprehend possible routes of van gene dissemination. In the current work, we present a comprehensive bioinformatic analysis aimed at mapping the occurrence of van genes beyond the Actinobacteria phylum—the most likely natural reservoir of van genes. We show that two additional classes of Gram-positive bacteria, Erysipelotrichia and Ktedonobacteria, as well as one class of Gram-negative bacteria, Anaerolineae, carry van genes. Additionally, we demonstrate that various new genera belonging to the classes Clostridia and Bacilli also carry van genes. The majority of discovered van loci are co-localized with MGE-related genes of various types. Finally, we propose a phylogeny-based scenario for the spread of van genes, unraveling a network of consequential horizontal gene transfer events linking the phylum Actinobacteria with the five other bacterial classes carrying van genes.

Heterologous Expression Reveals Ancient Properties of Tei3—A VanS Ortholog from the Teicoplanin Producer Actinoplanes teichomyceticus

“…vanHAXRS genes were experimentally shown to provide GPA resistance in (i) GPA-producing actinobacteria [ 34 ], (ii) actinobacterial GPA non-producers [ 31 ], (iii) GPA-resistant pathogens [ 28 ], and (iv) other soil bacteria [ 19 , 54 ]. In the majority of the known cases, the VanRS two-component regulatory system is utilized to sense extracellular GPAs [ 29 ] (or perhaps the GPA-lipid II complex [ 30 ]) and activate the expression of functional van genes.…”

“…Peculiarly, resistance mechanisms in GPA producers and pathogens are very similar [ 17 ]. It is likely that pathogens acquired GPA resistance genes from GPA producers, or more generally from non-producing actinobacteria, where GPA resistance determinants are abundant [ 18 , 19 ]. GPAs interact with d- alanyl- d- alanine ( d- Ala- d- Ala) termini of the nascent peptidoglycan (PG), impeding upstream transpeptidation and transglycosylation reactions and consequently blocking cell wall biosynthesis [ 20 ].…”