Emergence of vancomycin tolerance in Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae, the pneumococcus, is the most common cause of sepsis and meningitis. Multiple-antibiotic-resistant strains are widespread, and vancomycin is the antibiotic of last resort. Emergence of vancomycin resistance in this community-acquired bacterium would be catastrophic. Antibiotic tolerance, the ability of bacteria to survive but not grow in the presence of antibiotics, is a precursor phenotype to resistance. Here we show that loss of function of the VncS histidine kinase of a two-component sensor-regulator system in S. pneumoniae produced tolerance to vancomycin and other classes of antibiotic. Bacterial two-component systems monitor environmental parameters through a sensor histidine-kinase/phosphatase, which phosphorylates/dephosphorylates a response regulator that in turn mediates changes in gene expression. These results indicate that signal transduction is critical for the bactericidal activity of antibiotics. Experimental meningitis caused by the vncS mutant failed to respond to vancomycin. Clinical isolates tolerant to vancomycin were identified and DNA sequencing revealed nucleotide alterations in vncS. We conclude that broad antibiotic tolerance of S. pneumoniae has emerged in the community by a molecular mechanism that eliminates sensitivity to the current cornerstone of therapy, vancomycin.

Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia

“…The recent model suggested that Pep27, encoded upstream of the VncRS locus was secreted from the cell by the Vex123 transporter [14]. In this study, we elucidated the underlying immunological processes and identified VncRS, which is the vancomycin-resistant TCS [15] in serotype 2 of the D39 strain, to be responsible for fulminant inflammation and sepsis in mice, and as a key factor for lysis and sepsis. We additionally identified that mutations in pep27 VncRS abrogate inflammation and sepsis.…”

Molecular mechanisms and epidemiology of resistance in Streptococcus pneumoniae in the Middle East region

“…This mutation was thought to be the main mechanism behind vancomycin tolerance leading to autolytic activity suppression. A study conducted in the late 1990s reported that the vncS mutant not only exhibited vancomycin tolerance, but also was capable of developing tolerance to many other antibiotics, including quinolones and beta-lactams [65].…”

Multivalent Antibiotics via Metal Complexes: Potent Divalent Vancomycins against Vancomycin-Resistant Enterococci

“…[9][10][11][12][13][14][15][16][17][18] In the research of multivalency, the ligandreceptor pair of vancomycin (Van)-D-Ala-D-Ala has attracted a great deal of research attention because it relates to vancomycin [19][20][21][22] -resistant enterococci (VRE). 23, 24 Walsh and colleagues 21,[24][25][26][27] have deciphered the mechanism of vancomycin resistance: VRE mutates its terminal peptides from D-Ala-D-Ala to D-Ala-D-Lac (i.e., D-alanine-D-lactate), which has substantially lowered (∼10 3 times decrease) its affinity to Van. 25,26,28 Though Van self-associates to form homodimers upon binding to D-Ala-D-Ala, as elucidated by Williams et al, [29][30][31][32][33] this noncovalent dimerization of Van alone is insufficient to act against VRE.…”