Resistance to rifampicin: at the crossroads between ecological, genomic and medical concerns

Tupin, Audrey; Gualtieri, Maxime; Roquet-Banères, Françoise; Morichaud, Zakia; Brodolin, Konstantin; Leonetti, Jean-Paul

doi:10.1016/j.ijantimicag.2009.12.017

Cited by 102 publications

(83 citation statements)

References 48 publications

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“…Binding of rifampin to the RpoB molecule involves 12 amino acid residues. Mutagenesis of each of these residues, except for one, generates a resistant phenotype (52). The fact that we found Lac ϩ mutants repeatedly with the same nucleotide change at a much higher frequency than that of rifampin resistance indicates that the mutation frequency at this particular locus is increased compared to that for other loci in the genome, such as the rpoB gene.…”

Section: Transcriptome Analysis Of Lactose-utilizing L Lactis Mg1363mentioning

confidence: 68%

A Specific Mutation in the Promoter Region of the Silent cel Cluster Accounts for the Appearance of Lactose-Utilizing Lactococcus lactis MG1363

Solopova

Bachmann

Teusink

et al. 2012

Appl Environ Microbiol

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The Lactococcus lactis laboratory strain MG1363 has been described to be unable to utilize lactose. However, in a rich medium supplemented with lactose as the sole carbon source, it starts to grow after prolonged incubation periods. Transcriptome analyses showed that L. lactis MG1363 Lac ؉ cells expressed celB, encoding a putative cellobiose-specific phosphotransferase system (PTS) IIC component, which is normally silent in MG1363 Lac ؊ cells. Nucleotide sequence analysis of the cel cluster of a Lac ؉ isolate revealed a change from one of the guanines to adenine in the promoter region. We showed here that one particular mutation, taking place at increased frequency, accounts for the lactose-utilizing phenotype occurring in MG1363 cultures. The G-to-A transition creates a ؊10 element at an optimal distance from the ؊35 element. Thus, a fully active promoter is created, allowing transcription of the otherwise cryptic cluster. Nuclear magnetic resonance (NMR) spectroscopy results show that MG1363 Lac ؉ uses a novel pathway of lactose utilization. Lactococcus lactis is an industrially important lactic acid bacterium (LAB). It is the main constituent of cheese starter cultures and is used for its ability to rapidly convert the milk sugar lactose into lactic acid. Because of the economic importance of lactose fermentation, the metabolism of this sugar is being studied extensively.Two main systems of lactose uptake and metabolism have been described for LAB. The bioenergetically most efficient system in most strains is encoded by a plasmid and consists of the phosphoenolpyruvate:lactose phosphotransferase system (PEP-PTS Lac ; encoded by lacEF), phospho-␤-galactosidase (lacG), and the tagatose 6-phosphate (tagatose 6-P) pathway enzymes (lacABCD) (10). During uptake, lactose is phosphorylated at the galactose moiety and then hydrolyzed. The glucose moiety enters glycolysis, while galactose 6-phosphate is degraded via the tagatose 6-P pathway, consisting of galactose 6-phosphate isomerase (lacAB), tagatose 6-phosphate kinase (lacC), and 1,6-diphosphate aldolase (lacD). The generated triosephosphates are then directed to glycolysis. All glycolytic enzymes are encoded on the lactococcal chromosome. Another way to internalize lactose is provided by the chromosomally encoded lactose-specific permease (lacY)-␤-galactosidase (lacZ) system (21, 38). Internalized unphosphorylated lactose is cleaved by ␤-galactosidase (lacZ), and the resulting galactose molecule enters the Leloir pathway (54), while the glucose moiety is further metabolized by glycolytic enzymes. Genes coding for the galactose permease (GalP) and the Leloir pathway enzymes are clustered together in the gal operon. This pathway consists of reactions that are catalyzed by galactose mutarotase (GalM), galactokinase (GalK), galactose 1-phosphate uridylyltransferase (GalT), and UDP-galactose-4-epimerase (GalE) (14). The resulting glucose 1-phosphate is then converted to glucose 6-phosphate by ␣-phosphoglucomutase (PgmH) and directed to glycolysis (28). One of the main...

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Section: Transcriptome Analysis Of Lactose-utilizing L Lactis Mg1363mentioning

confidence: 68%

A Specific Mutation in the Promoter Region of the Silent cel Cluster Accounts for the Appearance of Lactose-Utilizing Lactococcus lactis MG1363

Solopova

Bachmann

Teusink

et al. 2012

Appl Environ Microbiol

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“…These covalent modifications occur on the critical hydroxyls of the 1-amino, 2-naphthol, 4-sulfonic acid (ansa) chain of rifamycins and thus make rifamycins unable to fit into the binding pocket on RNAP. Additional resistance mechanisms have been reported also (14)(15)(16).…”

mentioning

confidence: 80%

Structural basis of rifampin inactivation by rifampin phosphotransferase

Lin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Rifampin (RIF) is a first-line drug used for the treatment of tuberculosis and other bacterial infections. Various RIF resistance mechanisms have been reported, and recently an RIF-inactivation enzyme, RIF phosphotransferase (RPH), was reported to phosphorylate RIF at its C21 hydroxyl at the cost of ATP. However, the underlying molecular mechanism remained unknown. Here, we solve the structures of RPH from Listeria monocytogenes (LmRPH) in different conformations. LmRPH comprises three domains: an ATP-binding domain (AD), an RIF-binding domain (RD), and a catalytic His-containing domain (HD). Structural analyses reveal that the C-terminal HD can swing between the AD and RD, like a toggle switch, to transfer phosphate. In addition to its catalytic role, the HD can bind to the AD and induce conformational changes that stabilize ATP binding, and the binding of the HD to the RD is required for the formation of the RIF-binding pocket. A line of hydrophobic residues forms the RIF-binding pocket and interacts with the 1-amino, 2-naphthol, 4-sulfonic acid and naphthol moieties of RIF. The R group of RIF points toward the outside of the pocket, explaining the low substrate selectivity of RPH. Four residues near the C21 hydroxyl of RIF, His825, Arg666, Lys670, and Gln337, were found to play essential roles in the phosphorylation of RIF; among these the His825 residue may function as the phosphate acceptor and donor. Our study reveals the molecular mechanism of RIF phosphorylation catalyzed by RPH and will guide the development of a new generation of rifamycins.antibiotic resistance | rifampin | phosphotransferase | molecular mechanism | toggle switch

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“…Rifampin resistance in staphylococci is most frequently based on point mutations in the highly conserved regions of the rpoB gene, which encodes the beta subunit of the bacterial RNA polymerase, resulting in amino acid substitutions at or near the binding site for the drug (591,592). In a 2009 Swedish study, approximately 39% of PJI-related S. epidermidis isolates were found to be rifampin resistant (MIC 90 , Ͼ32 mg/liter) (499).…”

Section: S Epidermidis Ms-cons Mr-cons Cons S Epidermidis S Haemolmentioning

confidence: 99%

Coagulase-Negative Staphylococci

2014

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SUMMARY The definition of the heterogeneous group of coagulase-negative staphylococci (CoNS) is still based on diagnostic procedures that fulfill the clinical need to differentiate between Staphylococcus aureus and those staphylococci classified historically as being less or nonpathogenic. Due to patient- and procedure-related changes, CoNS now represent one of the major nosocomial pathogens, with S. epidermidis and S. haemolyticus being the most significant species. They account substantially for foreign body-related infections and infections in preterm newborns. While S. saprophyticus has been associated with acute urethritis, S. lugdunensis has a unique status, in some aspects resembling S. aureus in causing infectious endocarditis. In addition to CoNS found as food-associated saprophytes, many other CoNS species colonize the skin and mucous membranes of humans and animals and are less frequently involved in clinically manifested infections. This blurred gradation in terms of pathogenicity is reflected by species- and strain-specific virulence factors and the development of different host-defending strategies. Clearly, CoNS possess fewer virulence properties than S. aureus , with a respectively different disease spectrum. In this regard, host susceptibility is much more important. Therapeutically, CoNS are challenging due to the large proportion of methicillin-resistant strains and increasing numbers of isolates with less susceptibility to glycopeptides.

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Resistance to rifampicin: at the crossroads between ecological, genomic and medical concerns

Cited by 102 publications

References 48 publications

A Specific Mutation in the Promoter Region of the Silent cel Cluster Accounts for the Appearance of Lactose-Utilizing Lactococcus lactis MG1363

A Specific Mutation in the Promoter Region of the Silent cel Cluster Accounts for the Appearance of Lactose-Utilizing Lactococcus lactis MG1363

Structural basis of rifampin inactivation by rifampin phosphotransferase

Coagulase-Negative Staphylococci

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