Abstract
Group B Streptococcus (GBS; Streptococcus agalactiae) is a leading cause of sepsis in neonates and pregnant mothers worldwide. Whereas the hyper-virulent serogroup III clonal cluster 17 has been associated with neonatal disease and meningitis, serogroup III ST283 was recently implicated in invasive disease among non-pregnant adults in Asia. Here, through comparative genome analyses of invasive and non-invasive ST283 strains, we identified a truncated DNA-binding regulator of a two-component system in a non-invasive strain that was homologous to Bacillus subtilis bceR, encoding the bceRSAB response regulator, which was conserved among GBS strains. Using isogenic knockout and complementation mutants of the ST283 strain, we demonstrated that resistance to bacitracin and the human antimicrobial peptide cathelicidin LL-37 was reduced in the ΔbceR strain with MICs changing from 64 and 256 μg/ml to 0.25 and 64 μg/ml, respectively. Further, the ATP-binding cassette transporter was upregulated by sub-inhibitory concentrations of bacitracin in the wild-type strain. Upregulation of dltA in the wild-type strain was also observed and thought to explain the increased resistance to antimicrobial peptides. DltA, an enzyme involved in D-alanylation during the synthesis of wall teichoic acids, which mediates reduced antimicrobial susceptibility, was previously shown to be regulated by the bceR-type regulator in Staphylococcus aureus. In a murine infection model, we found that the ΔbceR mutation significantly reduced the mortality rate compared to that with the wild-type strain (p < 0.01). Moreover, this mutant was more susceptible to oxidative stress compared to the wild-type strain (p < 0.001) and was associated with reduced biofilm formation (p < 0.0001). Based on 2-DGE and mass spectrometry, we showed that downregulation of alkyl hydroperoxide reductase (AhpC), a Gls24 family stress protein, and alcohol dehydrogenase (Adh) in the ΔbceR strain might explain the attenuated virulence and compromised stress response. Together, we showed for the first time that the bceR regulator in GBS plays an important role in bacitracin and antimicrobial peptide resistance, virulence, survival under oxidative stress, and biofilm formation.
Highlights
Group B Streptococcus (GBS) is the leading cause of sepsis in neonates and pregnant mothers worldwide (Russell et al, 2017; Seale et al, 2017)
The bceR-like system of S. aureus was previously found to respond to vancomycin and polymyxin B, and the homologous proteins encoded by these genes were determined to mediate resistance to bacitracin and nisin in S. mutans and Lactococcus lactis, respectively (Tsuda et al, 2002; Kramer et al, 2006)
In GBS, we found that the deletion of bceR resulted in an increased sensitivity to bacitracin and human cathelicidin LL-37
Summary
Group B Streptococcus (GBS) is the leading cause of sepsis in neonates and pregnant mothers worldwide (Russell et al, 2017; Seale et al, 2017). Group B Streptococcus serotype III-4/ST283 strains have been implicated in invasive diseases in non-pregnant adults in Asia (Wilder et al, 2000; Chan et al, 2002; Ip et al, 2006, 2016; Kalimuddin et al, 2017) This ST283 type has been recently associated with an outbreak of invasive disease in adults in Singapore, which was suspected to be caused by the foodborne ingestion of contaminated freshwater fish as sushi (Kalimuddin et al, 2017). Over the last 15 years, GBS serotype III-4 strains have remained a single clone of ST283, possessing distinct surface protein genes and mobile genetic elements and exhibiting indistinguishable PFGE fingerprints (Ip et al, 2006), suggesting that GBS III-4 strains might be hyper-virulent and possess special genetic virulent determinants
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