Stenotrophomonas maltophilia: An Urgent Threat with Increasing Antibiotic Resistance

Liu, Jiaying; Xiang, Yanghui; Zhang, Ying

doi:10.1007/s00284-023-03524-5

Cited by 8 publications

(3 citation statements)

References 122 publications

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“…To determine potential treatment response of the S. muris strains, we also determined their antibiotic susceptibility to six commonly used antibiotics including ceftazidime, levofloxacin, colistin, polymyxin B, sulfamethoxazole/trimethoprim, minocyclineand ceftazidime for treatment of S. maltophilia infections [24]. The results of the antibiotic susceptibility testing for S1, S8 and S9 are listed in Table 3.…”

Section: S Muris Strains Are Highly Resistant To Last Resort Antibiot...mentioning

confidence: 99%

Stenotrophomonas muris- First discovered as an urgent human pathogen with strong virulence associated with bloodstream infections

Liu,

Dong,

et al. 2024

Preprint

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For the first time, Stenotrophomonas muris (S. muris) has been identified to be a likely human pathogen while studying the virulence of Stenotrophomonas maltophilia (S. maltophilia) clinical isolates. Previously, S. muris was only isolated from the intestines of mice but its pathogenic potential for humans has never been reported. In this work, the phenotype of S. muris virulence, the potential genes that encode higher virulence of S. muris, and host responses to S. muris infection were investigated for the first time. It was found by SYTOX Green staining, lactate dehydrogenase (LDH) release and Galleria mellonella survival assay and a mouse model of infection that S9 (S. muris no.9, isolated from the patient's bloodstream infection) was more virulent than both S8 (S. muris no.8, isolated from the patient's sputum) and S1 (S. maltophilia type strain ATCC13637), where S8 and S9 were subsequently identified as S. muris by whole genome sequencing analysis. Based on the GO and KEGG databases, part of the candidate genes which possibly encode higher virulence of S9 were identified, including virB6, dcm, hlyD, group_374, group_3203, group_3063, group_832, group_962, group_2016, group_2745, group_3011, group_849, group_1035 and group_1019. Transcriptome analysis of host cells (THP-1 cells) infected by S8 and S9 was performed to investigate the host responses to S. muris infections. It was found that the differentially expressed genes of the infected host cells (group S9 with strong virulence vs group S8 with weak virulence) showed that 12 candidate genes involved in ion transport function and calcium signaling pathway are down-regulated and needed special attention. Susceptibility testing indicates that the treatment regimen of S. muris infections needs to be different from that of S. maltophilia, further demonstrating the necessity of distinguishing these two pathogens. It is also shown that minocycline could be effective for treatment of infections of S. muris. This work highlights the need to pay more attention to S. muris in clinical setting which could be a human pathogen of high risk, as well as provides the basis for subsequent study on the virulence genes and pathogenic mechanisms of S. muris.

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Section: S Muris Strains Are Highly Resistant To Last Resort Antibiot...mentioning

confidence: 99%

Stenotrophomonas muris- First discovered as an urgent human pathogen with strong virulence associated with bloodstream infections

Liu,

Dong,

et al. 2024

Preprint

Self Cite

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“…Stenotrophomonas maltophilia is an opportunistic environmental bacterium that can cause broad-spectrum infections of the respiratory tract, soft tissue, urinary tract, eyes, and wounds. S. maltophilia infections are difficult to treat because the pathogen exhibits intrinsic and acquired resistance to a broad spectrum of antibiotics ( Liu et al., 2023 ). To adapt to diverse environments, S. maltophilia is equipped with several iron acquisition systems for the utilization of ferric iron, ferrous iron, hemin, ferric citrate, and Pseudomonas aeruginosa pyochelin ( Nas and Cianciotto, 2017 ; Kalidasan et al., 2018 ; Liao et al., 2022 ; Pan et al., 2022 ; Shih et al., 2022 ).…”

Section: Introductionmentioning

confidence: 99%

HemU and TonB1 contribute to hemin acquisition in Stenotrophomonas maltophilia

Liao,

Lu,

Yang

et al. 2024

Front. Cell. Infect. Microbiol.

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IntroductionThe hemin acquisition system is composed of an outer membrane TonB-dependent transporter that internalizes hemin into the periplasm, periplasmic hemin-binding proteins to shuttle hemin, an inner membrane transporter that transports hemin into the cytoplasm, and cytoplasmic heme oxygenase to release iron. Fur and HemP are two known regulators involved in the regulation of hemin acquisition. The hemin acquisition system of Stenotrophomonas maltophilia is poorly understood, with the exception of HemA as a TonB-dependent transporter for hemin uptake.MethodsPutative candidates responsible for hemin acquisition were selected via a homolog search and a whole-genome survey of S. maltophilia. Operon verification was performed by reverse transcription-polymerase chain reaction. The involvement of candidate genes in hemin acquisition was assessed using an in-frame deletion mutant construct and iron utilization assays. The transcript levels of candidate genes were determined using quantitative polymerase chain reaction.ResultsSmlt3896-hemU-exbB2-exbD2-tonB2 and tonB1-exbB1-exbD1a-exbD1b operons were selected as candidates for hemin acquisition. Compared with the parental strain, hemU and tonB1 mutants displayed a defect in their ability to use hemin as the sole iron source for growth. However, hemin utilization by the Smlt3896 and tonB2 mutants was comparable to that of the parental strain. HemA expression was repressed by Fur in iron-replete conditions and derepressed in iron-depleted conditions. HemP negatively regulated hemA expression. Like hemA, hemU was repressed by Fur in iron-replete conditions; however, hemU was moderately derepressed in response to iron-depleted stress and fully derepressed when hemin was present. Unlike hemA and hemU, the TonB1-exbB1-exbD1a-exbD1b operon was constitutively expressed, regardless of the iron level or the presence of hemin, and Fur and HemP had no influence on its expression.ConclusionHemA, HemU, and TonB1 contribute to hemin acquisition in S. maltophilia. Fur represses the expression of hemA and hemU in iron-replete conditions. HemA expression is regulated by low iron levels, and HemP acts as a negative regulator of this regulatory circuit. HemU expression is regulated by low iron and hemin levels in a hemP-dependent manner.

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“…The genus Stenotrophomonas includes at least 22 species of Gram-negative bacteria that are found in water, soil, and plant material ( https://lpsn.dsmz.de/genus/stenotrophomonas ) ( 1 – 4 ). Notable among the Stenotrophomonas species is Stenotrophomonas maltophilia , an opportunistic pathogen that causes, among other things, pneumonia and bacteremia ( 5 – 7 ). S. maltophilia is problematic in patients with cystic fibrosis (CF), where it increases the chance of lung exacerbations ( 8 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

Bactericidal effectors of the Stenotrophomonas maltophilia type IV secretion system: functional definition of the nuclease TfdA and structural determination of TfcB

Cobe,

Dey,

Minasov

et al. 2024

mBio

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Stenotrophomonas maltophilia expresses a type IV protein secretion system (T4SS) that promotes contact-dependent killing of other bacteria and does so partly by secreting the effector TfcB. Here, we report the structure of TfcB, comprising an N-terminal domain similar to the catalytic domain of glycosyl hydrolase (GH-19) chitinases and a C-terminal domain for recognition and translocation by the T4SS. Utilizing a two-hybrid assay to measure effector interactions with the T4SS coupling protein VirD4, we documented the existence of five more T4SS substrates. One of these was protein 20845, an annotated nuclease. A S. maltophilia mutant lacking the gene for 20845 was impaired for killing Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa . Moreover, the cloned 20845 gene conferred robust toxicity, with the recombinant E. coli being rescued when 20845 was co-expressed with its cognate immunity protein. The 20845 effector was an 899 amino-acid protein, comprised of a GHH-nuclease domain in its N-terminus, a large central region of indeterminant function, and a C-terminus for secretion. Engineered variants of the 20845 gene that had mutations in the predicted catalytic site did not impede E. coli , indicating that the antibacterial effect of 20845 involves its nuclease activity. Using flow cytometry with DNA staining, we determined that 20845, but not its mutant variants, confers a loss in DNA content of target bacteria. Database searches revealed that uncharacterized homologs of 20845 occur within a range of bacteria. These data indicate that the S. maltophilia T4SS promotes interbacterial competition through the action of multiple toxic effectors, including a potent, novel DNase. IMPORTANCE Stenotrophomonas maltophilia is a multi-drug-resistant, Gram-negative bacterium that is an emerging pathogen of humans. Patients with cystic fibrosis are particularly susceptible to S. maltophilia infection. In hospital water systems and various types of infections, S. maltophilia co-exists with other bacteria, including other pathogens such as Pseudomonas aeruginosa . We previously demonstrated that S. maltophilia has a functional VirB/D4 type VI protein secretion system (T4SS) that promotes contact-dependent killing of other bacteria. Since most work on antibacterial systems involves the type VI secretion system, this observation remains noteworthy. Moreover, S. maltophilia currently stands alone as a model for a human pathogen expressing an antibacterial T4SS. Using biochemical, genetic, and cell biological approaches, we now report both the discovery of a novel antibacterial nuclease (TfdA) and the first structural determination of a bactericidal T4SS effector (TfcB).

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Stenotrophomonas maltophilia: An Urgent Threat with Increasing Antibiotic Resistance

Cited by 8 publications

References 122 publications

Stenotrophomonas muris- First discovered as an urgent human pathogen with strong virulence associated with bloodstream infections

Stenotrophomonas muris- First discovered as an urgent human pathogen with strong virulence associated with bloodstream infections

HemU and TonB1 contribute to hemin acquisition in Stenotrophomonas maltophilia

Bactericidal effectors of the Stenotrophomonas maltophilia type IV secretion system: functional definition of the nuclease TfdA and structural determination of TfcB

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