Abstract
Bacteria have specific signaling systems to overcome selective pressure, such as exposure to antibiotics. The two-component system (TCS) plays an important role in the development of antibiotic resistance. Using the rice pathogen Burkholderia glumae BGR1 as a model organism, we showed that the GluS (BGLU_1G13350) – GluR (BGLU_1G13360) TCS, consisting of a sensor kinase and response regulator, respectively, contributes to β-lactam resistance through a distinct mechanism. Inactivation of gluS or gluR conferred resistance to β-lactam antibiotics in B. glumae, whereas wild-type (WT) B. glumae was susceptible to these antibiotics. In gluS and gluR mutants, the expression of genes encoding metallo-β-lactamases (MBLs) and penicillin-binding proteins (PBPs) was significantly higher than in the WT. GluR-His bound to the putative promoter regions of annotated genes encoding MBL (BGLU_1G21360) and PBPs (BGLU_1G13280 and BGLU_1G04560), functioning as a repressor. These results demonstrate that the potential to attain β-lactam resistance may be genetically concealed in the TCS, in contrast to the widely accepted view of the role of TCS in antibiotic resistance. Our findings provide a new perspective on antibiotic resistance mechanisms, and suggest a different therapeutic approach for successful control of bacterial pathogens.
Highlights
Irrational use of antibiotics contributes to the emergence of antibiotic-resistant pathogens, thereby promoting disease outbreaks
We previously reported that GluR regulates the expression of cell division genes in B. glumae, we reasoned that this two-component system (TCS) might be involved in antibiotic sensitivity as well
We examined the ability of the TCS null mutants to tolerate selected β-lactam antibiotics such as carbenicillin
Summary
Irrational use of antibiotics contributes to the emergence of antibiotic-resistant pathogens, thereby promoting disease outbreaks. GluS-GluR Mutations Confer β-Lactam Resistance response regulators subsequently undergo conformational modifications in order to become active, controlling the expression of target genes (Hoch, 2000). TCSs direct the process of antibiotic resistance through drug target modification, decreased influx, increased outflow, regulation of antibioticdegrading enzymes, biofilm formation, and stress induction (Tierney and Rather, 2019). TCSs reported to regulate antibiotic resistance include PhoP-PhoQ of Pseudomonas aeruginosa, which triggers resistance to polymyxin B (McPhee et al, 2006; Gooderham and Hancock, 2009), VanS-VanR of Enterococcus faecium and Streptomyces coelicolor, which reduces affinity to vancomycin (Arthur et al, 1992; Hong et al, 2008), and CreBCreC of Escherichia coli and VbrK-VbrR of Vibrio parahaemolyticus, which triggers β-lactam resistance through β-lactamase expression (Zamorano et al, 2014; Li et al, 2016). Our findings provide new insight into antibiotic resistance mechanisms, and suggest a novel therapeutic approach for successful control of bacterial pathogens
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