TY - JOUR
T1 - Ranking of persister genes in the same Escherichia coli genetic background demonstrates varying importance of individual persister genes in tolerance to different antibiotics
AU - Wu, Nan
AU - He, Lei
AU - Cui, Peng
AU - Wang, Wenjie
AU - Yuan, Youhua
AU - Liu, Shuang
AU - Xu, Tao
AU - Zhang, Shanshan
AU - Wu, Jing
AU - Zhang, Wenhong
AU - Zhang, Ying
N1 - Publisher Copyright:
© 2015 Wu, He, Cui, Wang, Yuan, Liu, Xu, Zhang, Wu, Zhang and Zhang.
PY - 2015
Y1 - 2015
N2 - Despite the identification of many genes and pathways involved in the persistence phenomenon of bacteria, the relative importance of these genes in a single organism remains unclear. Here, using Escherichia coli as a model, we generated mutants of 21 known candidate persister genes and compared the relative importance of these mutants in persistence to various antibiotics (ampicillin, gentamicin, norfloxacin, and trimethoprim) at different times. We found that oxyR, dnaK, sucB, relA, rpoS, clpB, mqsR, and recA were prominent persister genes involved in persistence to multiple antibiotics. These genes map to the following pathways: antioxidative defense pathway (oxyR), global regulators (dnaK, clpB, and rpoS), energy production (sucB), stringent response (relA), toxin-antitoxin (TA) module (mqsR), and SOS response (recA). Among the TA modules, the ranking order was mqsR, lon, relE, tisAB, hipA, and dinJ. Intriguingly, rpoS deletion caused a defect in persistence to gentamicin but increased persistence to ampicillin and norfloxacin. Mutants demonstrated dramatic differences in persistence to different antibiotics at different time points: some mutants (oxyR, dnaK, phoU, lon, recA, mqsR, and tisAB) displayed defect in persistence from early time points, while other mutants (relE, smpB, glpD, umuD, and tnaA) showed defect only at later time points. These results indicate that varying hierarchy and importance of persister genes exist and that persister genes can be divided into those involved in shallow persistence and those involved in deep persistence. Our findings suggest that the persistence phenomenon is a dynamic process with different persister genes playing roles of variable significance at different times. These findings have implications for improved understanding of persistence phenomenon and developing new drugs targeting persisters for more effective cure of persistent infections.
AB - Despite the identification of many genes and pathways involved in the persistence phenomenon of bacteria, the relative importance of these genes in a single organism remains unclear. Here, using Escherichia coli as a model, we generated mutants of 21 known candidate persister genes and compared the relative importance of these mutants in persistence to various antibiotics (ampicillin, gentamicin, norfloxacin, and trimethoprim) at different times. We found that oxyR, dnaK, sucB, relA, rpoS, clpB, mqsR, and recA were prominent persister genes involved in persistence to multiple antibiotics. These genes map to the following pathways: antioxidative defense pathway (oxyR), global regulators (dnaK, clpB, and rpoS), energy production (sucB), stringent response (relA), toxin-antitoxin (TA) module (mqsR), and SOS response (recA). Among the TA modules, the ranking order was mqsR, lon, relE, tisAB, hipA, and dinJ. Intriguingly, rpoS deletion caused a defect in persistence to gentamicin but increased persistence to ampicillin and norfloxacin. Mutants demonstrated dramatic differences in persistence to different antibiotics at different time points: some mutants (oxyR, dnaK, phoU, lon, recA, mqsR, and tisAB) displayed defect in persistence from early time points, while other mutants (relE, smpB, glpD, umuD, and tnaA) showed defect only at later time points. These results indicate that varying hierarchy and importance of persister genes exist and that persister genes can be divided into those involved in shallow persistence and those involved in deep persistence. Our findings suggest that the persistence phenomenon is a dynamic process with different persister genes playing roles of variable significance at different times. These findings have implications for improved understanding of persistence phenomenon and developing new drugs targeting persisters for more effective cure of persistent infections.
KW - Antibiotics
KW - Escherichia coli
KW - Knockout mutant
KW - Persistence
KW - Persister gene
KW - Ranking
UR - http://www.scopus.com/inward/record.url?scp=84946727512&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946727512&partnerID=8YFLogxK
U2 - 10.3389/fmicb.2015.01003
DO - 10.3389/fmicb.2015.01003
M3 - Article
C2 - 26483762
AN - SCOPUS:84946727512
SN - 1664-302X
VL - 6
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
IS - SEP
M1 - 01003
ER -