Differential regulation of L1 and L2 beta-lactamase expression in Stenotrophomonas maltophilia

Avison, Matthew B.; Higgins, Catherine S.; Ford, P. J.; Heldreich, Charlotte J. von; Walsh, Timothy R.; Bennett, Peter M.

doi:10.1093/jac/49.2.387

Cited by 53 publications

(38 citation statements)

References 8 publications

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“…The ␤-lactamase L1 is a metallo-␤-lactamase (352), and L2 is a clavulanic acid-sensitive cephalosporinase (353). Several studies have reported differential ␤-lactamase activities among S. maltophilia isolates (16,17,56,78,147,148,153,170,227,251,374). The L1 ␤-lactamase uses a Sec export system, while the L2 ␤-lactamase uses a Tat export system for periplasmic translocation (194,271).…”

Section: Antibiotic Resistancementioning

confidence: 99%

“…The isolation of S. maltophilia mutants and the generation of isogenic L1 and L2 gene knockout mutants have shown that ␤-lactamase L1 and L2 expressions are differentially regulated (16,148). The expression of the ␤-lactamases is controlled at the level of transcription by the ampR gene, positioned upstream of L2, as part of an ampR-L2 module (201,251).…”

Section: Antibiotic Resistancementioning

confidence: 99%

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Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

2012

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SUMMARY Stenotrophomonas maltophilia is an emerging multidrug-resistant global opportunistic pathogen. The increasing incidence of nosocomial and community-acquired S. maltophilia infections is of particular concern for immunocompromised individuals, as this bacterial pathogen is associated with a significant fatality/case ratio. S. maltophilia is an environmental bacterium found in aqueous habitats, including plant rhizospheres, animals, foods, and water sources. Infections of S. maltophilia can occur in a range of organs and tissues; the organism is commonly found in respiratory tract infections. This review summarizes the current literature and presents S. maltophilia as an organism with various molecular mechanisms used for colonization and infection. S. maltophilia can be recovered from polymicrobial infections, most notably from the respiratory tract of cystic fibrosis patients, as a cocolonizer with Pseudomonas aeruginosa . Recent evidence of cell-cell communication between these pathogens has implications for the development of novel pharmacological therapies. Animal models of S. maltophilia infection have provided useful information about the type of host immune response induced by this opportunistic pathogen. Current and emerging treatments for patients infected with S. maltophilia are discussed.

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Section: Antibiotic Resistancementioning

confidence: 99%

Section: Antibiotic Resistancementioning

confidence: 99%

Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

2012

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“…Hence, it is very likely that the L1 or L2 gene was externally acquired in either cluster A or B if the evolutionary rates are similar for the L1 and L2 genes. Avison et al presented data on the localization of the L1 and L2 genes in cells (1,2). Minkwitz and Berg have suggested that there is a reservoir of S. maltophilia strains in the natural environment (21).…”

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confidence: 99%

Isolation of Multidrug-Resistant Stenotrophomonas maltophilia from Cultured Yellowtail ( Seriola quinqueradiata ) from a Marine Fish Farm

Furushita

Okamoto

Maeda

et al. 2005

Appl Environ Microbiol

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Six strains of multidrug-resistant Stenotrophomonas maltophilia were isolated from cultured yellowtail. The strains were divided into two clusters based on the 16S rRNA genes, and all of them contained L1 metallo-␤-lactamase and L2 ␤-lactamase genes. Differences in the intercluster divergence between the lactamase genes suggest that horizontal transfer of the genes occurred.Stenotrophomonas maltophilia is a multidrug-resistant bacterium that has been isolated from numerous terrestrial environments (3,7,12,18) and recently has emerged as a nosocomial pathogen in clinical environments (8,13,19,30). Although the phylogenetic relationship between environmental and clinical strains has been examined, no clear distinction has been established yet.We isolated six strains of S. maltophilia, which were identified with API 20NE (BioMerieux, La Balm, France), from yellowtail (Seriola quinqueradiata) cultured in a fish farm located at the southern tip of Japan (14). All six strains grew on Muller-Hinton agar (Becton Dickinson Microbiology Systems, Cockeysville, MD) supplemented with either ampicillin (32 g ml Ϫ1 ) or panipenem (32 g ml Ϫ1 ). The strains were also resistant to cefotaxime and ceftazidime, as determined by susceptibility tests with Sensi-Disks (Showa, Tokyo, Japan). Although the strains grew in a seawater-based medium, the growth rates in this medium were 0.6-fold lower than those with no NaCl. Hence, we concluded that the strains are not indigenous to marine environments. The resistance to ampicillin seemed to be a factor that could induce the presence of S. maltophilia in the fish farm, since medication with ampicillin was used in the previous year according to the fish farmer. Samuelsen et al. have reported persistence of drug-resistant bacteria even in the absence direct selection (28). NaCl may have been a factor in the survival. Resistance to panipenem, cefotaxime, and ceftazidime probably did not play a role in the distribution of the strains, since none of these antibiotics can be used in aquaculture. Rather, the resistance to these drugs suggests that the strains were derived from clinical environments.16S rRNA gene sequences of the six strains were determined for the phylogenetic analysis by a method described previously (14). The phylogenetic analysis divided the strains into two distinct clusters, cluster A (strains BL-9, BL-10, BL-15, and BL-16) and cluster B (strains BL-12 and BL-13), and both of the clusters were included in group I described by Hauben et al., which is comprised mainly of clinical and environmental strains (15).PCR amplification with forward primer 5Ј-CACACCTGGC AGATCGGCAC-3Ј and reverse primer 5Ј-GCCGCATCCGC GTAGGC-3Ј at an annealing temperature of 65°C was used to amplify L1 metallo-␤-lactamase (L1), which can degrade carbapenems (23,24,33). L2 serine ␤-lactamase (L2), which cannot degrade carbapenems (23, 32), was PCR amplified with forward primer 5Ј-CGATTCCTGCAGTTCAGT-3Ј and reverse primer 5Ј-CGGTTACCTCATCCGATC-3Ј at an annealing temperature of 55°C. No differences were foun...

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“…This also explains why S. maltophilia clinical isolates in our worldwide collection that are known to express ␤-lactamase constitutively at high levels (11,22) are no less susceptible to the lactivicin derivatives than are isolates with normally inducible ␤-lactamases (Table 2). Indeed, to confirm this, we tested four L1/L2-hyperproducing mutants previously derived from S. maltophilia K279a (22,27,29) and found that the MICs of both lactivicin derivatives against K279a and these mutants are the same (32 and Յ0.031 g · ml Ϫ1 , respectively, for LTV13 and LTV17). Conclusions.…”

Section: Resultsmentioning

confidence: 76%

Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates

Calvopiña

Umland

Rydzik

et al. 2016

Antimicrob Agents Chemother

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bAcetamido derivatives of the naturally antibacterial non-␤-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by ␤-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of the LTV lactone with a catechol-type siderophore increases potency 1,000-fold against Stenotrophomonas maltophilia, a species renowned for its insusceptibility to antimicrobials. The MIC 90 of modified lactone compound 17 (LTV17) against a global collection of extensively drug-resistant clinical S. maltophilia isolates was 0.063 g · ml ؊1 . Sideromimic modification does not reduce the ability of LTVs to induce production of the L1 and L2 ␤-lactamases in S. maltophilia and does not reduce the rate at which LTVs are hydrolyzed by L1 or L2. We conclude, therefore, that lactivicin modification with a siderophore known to be preferentially used by S. maltophilia substantially increases penetration via siderophore uptake. LTV17 has the potential to be developed as a novel antimicrobial for treatment of infections by S. maltophilia. More generally, our work shows that sideromimic modification in a species-targeted manner might prove useful for the development of narrow-spectrum antimicrobials that have reduced collateral effects. L activicin (LTV) is highly unusual in that it is the only non-␤-lactam natural product known to target penicillin binding proteins (PBPs). Unlike the ␤-lactams, which remain the most important antimicrobial class, lactivicin contains cycloserine and ␥-lactam motifs, but like the ␤-lactams, lactivicin reacts covalently with PBPs to form a stable acyl-enzyme complex (1) ( Fig. 1A and B). However, lactivicin has poor penetration into Gram-negative bacteria and is susceptible to at least some ␤-lactamase enzymes (2-4). A deeper understanding of the interactions between lactivicin and its derivatives and their various enzyme targets has led to the rational design of synthetic derivatives with higher potency against bacteria and reduced susceptibility to ␤-lactamases (1, 5, 6), including LTV13, which has the "ATMO"-type side chain (6) (Fig. 1C). Recently, it has been shown that sideromimic modification of the LTV ␥-lactone (4) results in more-favorable 50% inhibitory concentrations (IC 50 s) against Pseudomonas aeruginosa PBPs and improved penetration into P. aeruginosa strain PAO1 via interaction with the siderophore receptors and uptake systems of this strain. One of these lactivicin derivatives is phthalimide-conjugated compound 17 (here referred to as LTV17) (Fig. 1C) (6).Here we describe the activity of lactivicin derivatives against Stenotrophomonas maltophilia, which is an important nosocomial pathogen, primarily causing bloodstream and respiratory tract infections in severely debilitated patients. S. maltophilia also causes sporadic urinary tract and ocular infections and is a colonizer of the lungs of a significant proportion of adult patients with cystic fibrosis. Clinical isolates of S. malt...

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Differential regulation of L1 and L2 beta-lactamase expression in Stenotrophomonas maltophilia

Cited by 53 publications

References 8 publications

Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

Isolation of Multidrug-Resistant Stenotrophomonas maltophilia from Cultured Yellowtail ( Seriola quinqueradiata ) from a Marine Fish Farm

Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates

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