Gram positive pathogens are a significant cause of healthcare-associated infections, with Staphylococci and Enterococci being the most prevalent ones. Vancomycin, a last resort glycopeptide, is used to fight these bacteria but the emergence of resistance against this drug leaves some patients with few therapeutic options. To counter this issue, new generations of antibiotics have been developed but resistance has already been reported. In this article, we review the strategies in place or in development to counter vancomycin-resistant pathogens. First, an overview of traditional antimicrobials already on the market or in the preclinical or clinical pipeline used individually or in combination is summarized. The second part focuses on the non-traditional antimicrobials, such as antimicrobial peptides, bacteriophages and nanoparticles. The conclusion is that there is hitherto no substitute equivalent to vancomycin. However, promising strategies based on drugs with multiple mechanisms of action and treatments based on bacteriophages possibly combined with conventional antibiotics are hoped to provide treatment options for vancomycin-resistant Gram-positive pathogens.

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.