Opposite effect of vancomycin and D-Cycloserine combination in both vancomycin resistant Staphylococcus aureus and enterococci

Abstract

The increasing spread of antibiotic resistant bacteria is a major human health concern. The challenging development of new effective antibiotics has led to focus on seeking synergistic antibiotic combinations. Vancomycin (VAN) is a glycopeptide antibiotic used to treat Staphylococcus aureus and enterococci infections. It is targeting D-Alanyl-D-Alanine dimers during peptidoglycan biosynthesis. D-cycloserine (DCS) is a D-Alanine analogue that targets peptidoglycan biosynthesis by inhibiting D-Alanine:D-Alanine ligase (Ddl). The VAN-DCS combination was found to be synergistic in VAN resistant S. aureus strains lacking van genes cluster. We hypothesize that this combination leads to opposite effects in S. aureus and enterococci strains harboring van genes cluster where VAN resistance is conferred by the synthesis of modified peptidoglycan precursors ending in D-Alanyl-D-Lactate. The calculated Fractional Inhibitory Concentration of VAN-DCS combination in a van- vancomycin-intermediate, VanA type, and VanB type strains were 0.5, 5 and 3, respectively. As a result, VAN-DCS combination leads to synergism in van-lacking strains, and to antagonism in strains harboring van genes cluster. The VAN-DCS antagonism is due to a mechanism that we named van-mediated Ddl inhibition bypass. Our results show that antibiotic combinations can lead to opposite effects depending on the genetic backgrounds.

A Self‐Powered Wound Dressing Based on “Lock‐ON/OFF” Drug Release Combined Electric Stimulus Therapy for Accelerated Infected Wound Healing

“…VAN can directly bind to the end‐end of the cell wall peptide poly glucose anterior bodies, the end D‐prize‐D‐alanine, to prevent the action of the transpose of the peptide holystones, and interfere with the cross‐connection of the bacterial cell wall peptide anterior body, so that the cell wall cannot form a 3D space structure and sterilize. [ 22 ]…”

Metabolic Profiles of Clinical Isolates of Drug-Susceptible and Multidrug-Resistant Mycobacterium tuberculosis: A Metabolomics-Based Study

“…D-alanyl-D-alanine is a dipeptide comprising D-alanine with a D-alanyl residue attached to the alpha-nitrogen. 13 It is an essential component of the intracellular peptidoglycan precursor, uridine diphosphate-N-acetylcarbamate-pentapeptide, 14 which is vital for the survival of pathogens by maintaining the integrity of bacterial cell walls 15 , 16 through cross-linking peptidoglycan chains. 17 Inhibition of D-alanine-D-alanine ligase ( Ddl ) would directly lead to a dramatic decrease of the strength of the bacterial cell wall, potentially leading to bacterial cell rupture.…”

Discovery of novel antibacterial agents: Recent developments in D‐alanyl‐D‐alanine ligase inhibitors

“…D‐alanyl‐D‐alanine ligase (Ddl, EC 6.3.2.4) is an indispensable adenosine triphosphate (ATP)‐dependent bacterial enzyme involved in the biosynthesis of peptidoglycan, which catalyzes the ligation of two D‐alanine molecules into one D‐alanyl‐D‐alanine dipeptide (D‐Ala‐D‐Ala; Pederick et al., 2020; Tytgat, Colacino, et al., 2009; Tytgat, Vandevuer, et al., 2009; Walsh, 1989). This dipeptide is an essential component of the intracellular peptidoglycan precursor, uridine diphospho‐ N ‐acetylmuramic acid (UDP‐MurNAc)‐pentapeptide (Boudrioua et al., 2020; Van Heijenoort, 2001), which maintains the integrity of the bacterial cell wall by cross‐linking the peptidoglycan chain (Hrast et al., 2012), and is crucial for the survival of pathogens (Fakhar et al., 2016; Gholizadeh et al., 2001; Halouska et al., 2014; Mullins et al., 1990; Zhang et al., 2018). Inhibition of Ddl directly leads to a sharp decrease in the strength of the bacterial cell wall, which may lead to the rupture of the bacterial cell (Chen et al., 2019).…”