GlpD and PlsB Participate in Persister Cell Formation in Escherichia coli

Abstract

Bacterial populations produce dormant persister cells that are resistant to killing by all antibiotics currently in use, a phenomenon known as multidrug tolerance (MDT). Persisters are phenotypic variants of the wild type and are largely responsible for MDT of biofilms and stationary populations. We recently showed that a hipBA toxin/antitoxin locus is part of the MDT mechanism in Escherichia coli. In an effort to find additional MDT genes, an E. coli expression library was selected for increased survival to ampicillin. A clone with increased persister production was isolated and was found to overexpress the gene for the conserved aerobic sn-glycerol-3-phosphate dehydrogenase GlpD. The GlpD overexpression strain showed increased tolerance to ampicillin and ofloxacin, while a strain with glpD deleted had a decreased level of persisters in the stationary state. This suggests that GlpD is a component of the MDT mechanism. Further genetic studies of mutants affected in pathways involved in sn-glycerol-3-phosphate metabolism have led to the identification of two additional multidrug tolerance loci, glpABC, the anaerobic sn-glycerol-3-phosphate dehydrogenase, and plsB, an snglycerol-3-phosphate acyltransferase.

Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies

“…PlsB converts G3P to 1-acyl-G3P, an essential precursor of the phospholipid biosynthesis pathway (Lin, 1976). Possibly, these enzymes affect persister formation or resuscitation by modulating cellular G3P levels (Spoering et al, 2006). If and how these findings are connected to fosfomycin resistance remains to be determined.…”

“…Screening of an E. coli overexpression library led to the discovery of glpD and plsB as persistence genes (Spoering et al, 2006). GlpD is a G3P dehydrogenase involved in the catabolism of glycerol.…”

Senescence can explain microbial persistence

“…(The genetic bases for senescence and persistence are just beginning to emerge; see, for example, Nystrom, 2005;Vásquez-Laslop et al, 2006;Spoering et al, 2006. ) In reference to the third assumption, we can interpret cell division as a new, youthful cell being born from an old one.…”

A persistent problem

“…As De Groote et al (2011) note, their finding implicating an organic phosph[on]ate in persistence formation may be related to the observation that deletion of the E. coli gene glpD, encoding sn-glycerol-3-phosphate dehydrogenase, leads to a reduction in persistence (Spoering et al, 2006). In the glpD deletion strain, it appears that high levels of G3P (caused by lack of catabolism by GlpD) plus derepression of the Glp regulon (which is induced by G3P interacting with the GlpR repressor of the regulon) lead to suppression of the formation or maintenance of persisters.…”

“…Perhaps the putative organic phosph[on]ate promoter of persistence does so by competing with G3P in its role of reducing persistence, for example by preventing its interaction with GlpR. However, Spoering et al (2006) found that, in E. coli, deletion of glpT (which is part of the Glp regulon) does not reduce persistence (Spoering et al, 2006) as it does in P. aeruginosa (De Groote et al, 2011). But this may be explained by the fact that, in E. coli, there are several possible transporters for G3P, with Ugp being the main transporter for G3P under phosphate starvation conditions (Xavier et al, 1995), while in P. aeruginosa, GlpT is likely to be the only transporter for G3P, as no orthologues for ugpA or ugpB are found in P. aeruginosa.…”