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Molecular Characterization of Legionellosis Drug Target Candidate Enzyme Phosphoglucosamine Mutase from Legionella pneumophila (strain Paris): An In Silico Approach.

ABSTRACT: The harshness of legionellosis differs from mild Pontiac fever to potentially fatal Legionnaire's disease. The increasing development of drug resistance against legionellosis has led to explore new novel drug targets. It has been found that phosphoglucosamine mutase, phosphomannomutase, and phosphoglyceromutase enzymes can be used as the most probable therapeutic drug targets through extensive data mining. Phosphoglucosamine mutase is involved in amino sugar and nucleotide sugar metabolism. The purpose of this study was to predict the potential target of that specific drug. For this, the 3D structure of phosphoglucosamine mutase of Legionella pneumophila (strain Paris) was determined by means of homology modeling through Phyre2 and refined by ModRefiner. Then, the designed model was evaluated with a structure validation program, for instance, PROCHECK, ERRAT, Verify3D, and QMEAN, for further structural analysis. Secondary structural features were determined through self-optimized prediction method with alignment (SOPMA) and interacting networks by STRING. Consequently, we performed molecular docking studies. The analytical result of PROCHECK showed that 95.0% of the residues are in the most favored region, 4.50% are in the additional allowed region and 0.50% are in the generously allowed region of the Ramachandran plot. Verify3D graph value indicates a score of 0.71 and 89.791, 1.11 for ERRAT and QMEAN respectively. Arg419, Thr414, Ser412, and Thr9 were found to dock the substrate for the most favorable binding of S-mercaptocysteine. However, these findings from this current study will pave the way for further extensive investigation of this enzyme in wet lab experiments and in that way assist drug design against legionellosis.

SUBMITTER: Hasan A

PROVIDER: S-EPMC4330265 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Molecular Characterization of Legionellosis Drug Target Candidate Enzyme Phosphoglucosamine Mutase from Legionella pneumophila (strain Paris): An In Silico Approach.

Hasan Anayet A Mazumder Habibul Hasan HH Khan Arif A Hossain Mohammad Uzzal MU Chowdhury Homaun Kabir HK

Genomics & informatics 20141231 4

The harshness of legionellosis differs from mild Pontiac fever to potentially fatal Legionnaire's disease. The increasing development of drug resistance against legionellosis has led to explore new novel drug targets. It has been found that phosphoglucosamine mutase, phosphomannomutase, and phosphoglyceromutase enzymes can be used as the most probable therapeutic drug targets through extensive data mining. Phosphoglucosamine mutase is involved in amino sugar and nucleotide sugar metabolism. The ...[more]

PMID: 25705169

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Project description:The Legionella Reference Center in Japan collected 427 Legionella clinical isolates between 2008 and 2016, including 7 representative isolates from corresponding outbreaks. The collection included 419 Legionella pneumophila isolates, of which 372 belonged to serogroup 1 (SG1) (87%) and the others belonged to SG2 to SG15 except for SG7 and SG11, and 8 isolates of other Legionella species (Legionella bozemanae, Legionella dumoffii, Legionella feeleii, Legionella longbeachae, Legionella londiniensis, and Legionella rubrilucens). L. pneumophila isolates were genotyped by sequence-based typing (SBT) and represented 187 sequence types (STs), of which 126 occurred in a single isolate (index of discrimination of 0.984). These STs were analyzed using minimum spanning tree analysis, resulting in the formation of 18 groups. The pattern of overall ST distribution among L. pneumophila isolates was diverse. In particular, some STs were frequently isolated and were suggested to be related to the infection sources. The major STs were ST23 (35 isolates), ST120 (20 isolates), and ST138 (16 isolates). ST23 was the most prevalent and most causative ST for outbreaks in Japan and Europe. ST138 has been observed only in Japan, where it has caused small-scale outbreaks; 81% of those strains (13 isolates) were suspected or confirmed to infect humans through bath water sources. On the other hand, 11 ST23 strains (31%) and 5 ST120 strains (25%) were suspected or confirmed to infect humans through bath water. These findings suggest that some ST strains frequently cause legionellosis in Japan and are found under different environmental conditions.IMPORTANCELegionella pneumophila serogroup 1 (SG1) is the most frequent cause of legionellosis. Our previous genetic analysis indicated that SG1 environmental isolates represented 8 major clonal complexes, consisting of 3 B groups, 2 C groups, and 3 S groups, which included major environmental isolates derived from bath water, cooling towers, and soil and puddles, respectively. Here, we surveyed clinical isolates collected from patients with legionellosis in Japan between 2008 and 2016. Most strains belonging to the B group were isolated from patients for whom bath water was the suspected or confirmed source of infection. Among the isolates derived from patients whose suspected infection source was soil or dust, most belonged to the S1 group and none belonged to the B or C groups. Additionally, the U group was discovered as a new group, which mainly included clinical isolates with unknown infection sources.

Project description:Bacterial persisters are a transient subpopulation of non-growing, antibiotic-tolerant cells. There is increasing evidence that bacterial persisters play an important role in treatment failure leading to recurring infections and promoting the development of antibiotic resistance. Current research reveals that recurring legionellosis is often the result of relapse rather than reinfection and suggests that the mechanism of bacterial persistence may play a role. The development of single-cell techniques such as the Timerbac system allows us to identify potential persister cells and investigate their physiology. Here, we tested the persister forming capacity of 7 pairs of Legionella pneumophila (Lp) clinical isolates, with isolate pairs corresponding to two episodes of legionellosis in the same patient. We distinguished non-growing subpopulations from their replicating counterparts during infection in an amoeba model. Imaging flow cytometry allowed us to identify single non-growing bacteria within amoeba cells 17 h post-infection, thus corresponding to this subpopulation of potential persister cells. Interestingly the magnitude of this subpopulation varies between the 7 pairs of Lp clinical isolates. Biphasic killing kinetics using ofloxacin stress confirmed the persister development capacity of ST1 clinical isolates, highlighting enhanced persister formation during the host cell infection. Thus, persister formation appears to be strain or ST (sequence type) dependent. Genome sequence analysis was carried out between ST1 clinical isolates and ST1 Paris. No genetic microevolution (SNP) linked to possible increase of persistence capacity was revealed among all the clones tested, even in clones issued from two persistence cycle experiments, confirming the transient reversible phenotypic status of persistence. Treatment failure in legionellosis is a serious issue as infections have a 5-10% mortality rate, and investigations into persistence in a clinical context and the mechanisms involved may allow us to combat this issue.

Dataset Information

Molecular Characterization of Legionellosis Drug Target Candidate Enzyme Phosphoglucosamine Mutase from Legionella pneumophila (strain Paris): An In Silico Approach.

Publications

Molecular Characterization of Legionellosis Drug Target Candidate Enzyme Phosphoglucosamine Mutase from Legionella pneumophila (strain Paris): An In Silico Approach.

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