Urinary tract infections (UTIs) and catheter-associated UTIs (CAUTIs) are the principal hospital-acquired infections.
is characterized by several virulence factors able to promote adhesion and ...biofilm formation and ameliorate the colonization of urinary tract and the formation of crystalline biofilms on the abiotic surface of the urinary catheters. Since, to date, the role of
in the etiopathogenesis of different types of urinary tract infections is not well established, in this study we sought to characterize two different clinically isolated strains of
(PM1 and PM2) with distinctive phenotypes and analyzed various virulence factors possibly implicated in the ability to induce UTIs and CAUTIs. In particular, we analyzed motility, biofilm formation both on abiotic and biotic surfaces of PM1 and PM2 and paralleled these parameters with the ability to induce an inflammatory response in an epithelial cell model. Results showed that PM1 displayed major motility and a capacity to form biofilm and was associated with an anti-inflammatory response of host cells. Conversely, PM2 exhibited lack motility and a had slower organization in biofilm but promoted an increase of proinflammatory cytokine expression in infected epithelial cells. Our study provides data useful to start uncovering the pathologic basis of
-associated urinary infections. The evidence of different virulence factors expressed by PM1 and PM2 highlights the possibility to use precise and personalized therapies targeting specific virulence pathways.
Genetic features associated with the blaNDM-1 gene were investigated in 6 Escherichia coli, 7 Klebsiella pneumoniae, 1 Citrobacter freundii, 1 Proteus mirabilis, and 1 Providencia stuartii isolate of ...worldwide origin. Clonal diversity was observed for both E. coli and K. pneumoniae. The blaNDM-1 gene was carried by different plasmid types (IncA/C, IncF, IncL/M, or untypeable) and was likely chromosome borne in two isolates. The blaNDM-1 plasmids coharbored a variety of resistance determinants, including β-lactamase genes, quinolone resistance genes, and 16S RNA methylase genes.
Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 ...inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.
Medical devices, such as contact lenses, bring bacteria in direct contact with human cells. Consequences of these host-pathogen interactions include the alteration of mammalian cell surface ...architecture and induction of cellular death that renders tissues more susceptible to infection. Gram-negative bacteria known to induce cellular blebbing by mammalian cells, Pseudomonas and Vibrio species, do so through a type III secretion system-dependent mechanism. This study demonstrates that a subset of bacteria from the Enterobacteriaceae bacterial family induce cellular death and membrane blebs in a variety of cell types via a type V secretion-system dependent mechanism. Here, we report that ShlA-family cytolysins from Proteus mirabilis and Serratia marcescens were required to induce membrane blebbling and cell death. Blebbing and cellular death were blocked by an antioxidant and RIP-1 and MLKL inhibitors, implicating necroptosis in the observed phenotypes. Additional genetic studies determined that an IgaA family stress-response protein, GumB, was necessary to induce blebs. Data supported a model where GumB and shlBA are in a regulatory circuit through the Rcs stress response phosphorelay system required for bleb formation and pathogenesis in an invertebrate model of infection and proliferation in a phagocytic cell line. This study introduces GumB as a regulator of S. marcescens host-pathogen interactions and demonstrates a common type V secretion system-dependent mechanism by which bacteria elicit surface morphological changes on mammalian cells. This type V secretion-system mechanism likely contributes bacterial damage to the corneal epithelial layer, and enables access to deeper parts of the tissue that are more susceptible to infection.
In this study, we aimed to determine the interspecies interactions between Proteus mirabilis and Candida albicans. Mono and dual-species biofilms were grown in a microtiter plate and metabolomic ...analysis of the biofilms was performed. The effects of togetherness of two species on the expression levels of candidal virulence genes and urease and swarming activities of P.mirabilis were investigated. The growth of C.albicans was inhibited by P.mirabilis whereas the growth and swarming activity of P.mirabilis were increased by C.albicans. The inhibition of Candida cell growth was found to be biofilm specific. The alteration was not detected in urease activity. The expressions of EFG1, HWP1 and SAP2 genes were significantly down-regulated, however, LIP1 was upregulated by P.mirabilis. In the presence of P.mirabilis carbonhydrates, amino acids, polyamine and lipid metabolisms were altered in C.albicans. Interestingly, the putrescine level was increased up to 230 fold in dual-species biofilm compared to monospecies C.albicans biofilm. To our knowledge, this is the first study to investigate the impact of each microbial pathogen on the dual microbial environment by integration of metabolomic data.
•Clonal outbreak caused by multidrug- and imipenem-resistant Proteus mirabilis producing VIM-4 metallo-β-lactamase (MBL).•First documentation of VIM-4 MBL in P. mirabilis and first hospital outbreak ...caused by a MBL-producing P. mirabilis strain.•Outbreak (July 2015 to February 2016) involved 14 patients hospitalised in a Greek tertiary-care hospital.•Resistome analysis showed the presence of an IncQ1 plasmid harbouring the blaVIM-4 and blaTEM-2 genes.•Eighteen resistance genes encoding resistance to β-lactams, aminoglycosides, trimethoprim, sulfonamides and lincosamides.
Carbapenem-resistant Enterobacterales have become a major public-health issue worldwide. Here we report an outbreak caused by a clonal multidrug-resistant Proteus mirabilis strain producing VIM-4 metallo-β-lactamase (MBL) and TEM-2 β-lactamase in a Greek tertiary-care hospital. From July 2015 to February 2016, 27 imipenem-resistant P. mirabilis isolates were recovered from 14 patients hospitalised in two intensive care units (ICUs) and the internal medicine department in AHEPA University Hospital, Thessaloniki. The isolates were either susceptible or resistant to meropenem and were resistant to all remaining β-lactams except aztreonam. Phenotypic and molecular analysis revealed that all of the isolates harboured a blaVIM-4 MBL gene. Resistome analysis of a representative isolate showed the presence of an IncQ1 plasmid harbouring the blaVIM-4 carbapenemase and blaTEM-2 β-lactamase genes among resistance genes coding for resistance to β-lactams, aminoglycosides, trimethoprim, sulfonamides and lincosamides. Genotyping by pulsed-field electrophoresis (PFGE) revealed that the isolates were epidemiologically related. After recovery of the index carbapenemase-producing P. mirabilis clinical isolate, infection control measures were intensified in the affected departments. Rectal sampling for carbapenem-resistant bacteria was initiated on a weekly basis among patients admitted to the general ICU. The outbreak was finally interrupted 6 months later in February 2016. This is the first documentation of the blaVIM-4 MBL gene in P. mirabilis as well as the first hospital outbreak caused by a MBL-producing P. mirabilis strain.
In this study, we analyzed the molecular epidemiology of extended-spectrum β-lactamase (ESBL)-producing Proteus mirabilis isolates collected from the central region of Japan.
Between 2005 and 2012, ...820 clinical P. mirabilis isolates were obtained from ten acute care hospitals in Japan. We characterized ESBL confirmatory test-positive isolates by sequencing the ESBL genes and their flanking regions, detecting plasmid replicons, and performing pulsed-field gel electrophoresis (PFGE).
Ninety-six isolates (12%) were positive according to the ESBL confirmatory test; all these isolates possessed bla
with the same flanking structure of upstream ΔISEcp1 and a downstream region identical to downstream bla
. IncT was the prevalent, and only, replicon found in 63 isolates. PFGE analysis detected eight clusters with more than one isolate, among which three included 56 isolates and six included isolates from multiple hospitals.
CTX-M-2-producing P. mirabilis with an identical genetic structure flanking bla
is dominant in this Japanese region, and there is evidence for the clonal spread of isolates.
To characterize MDR genomic islands related to Salmonella genomic island 1 (SGI1) and Proteus genomic island 1 (PGI1) in Proteus mirabilis from human and animal sources in France in light of the ...previously reported cases.
A total of 52 and 46 P. mirabilis clinical strains from human and animal sources, respectively, were studied for the period 2010-13. MDR was assessed by antimicrobial susceptibility testing, PCR detection of SGI1 and PGI1 and PCR mapping of the MDR regions. The diversity of the SGI1/PGI1-positive P. mirabilis strains was assessed by PFGE.
Twelve P. mirabilis strains (5 humans and 7 dogs) were found to harbour an MDR island related to SGI1 or PGI1. Among them, several SGI1 variants were identified in diverse P. mirabilis genetic backgrounds. The variant SGI1-V, which harbours the ESBL bla VEB-6 gene, was found in closely genetically related human and dog P. mirabilis strains. The recently described PGI1 element was also identified in human and dog strains. Finally, one strain harboured a novel SGI genomic island closely related to SGI1 and SGI2 without an insertion of the MDR region.
This study reports for the first time, to our knowledge, SGI1-positive and PGI1-positive P. mirabilis strains from dogs in France. The genetic diversity of the strains suggests several independent horizontal acquisitions of these MDR elements. The potential transmission of SGI1/PGI1-positive P. mirabilis strains between animals and humans is of public health concern, notably with regard to the spread of ESBL and carbapenemase genes, i.e. bla VEB-6 and bla NDM-1.
Extended-spectrum beta-lactamases (ESBLs), AmpC-type beta-lactamases (ACBLs) and carbapenemases are among the most important resistance mechanisms in Enterobacteriaceae. This study investigated the ...presence of these resistance mechanisms in consecutive non-replicate isolates of Escherichia coli (n = 2,352), Klebsiella pneumoniae (n = 697), and Proteus mirabilis (n = 275) from an Italian nationwide cross-sectional survey carried out in October 2013. Overall, 15.3% of isolates were non-susceptible to extended-spectrum cephalosporins but susceptible to carbapenems (ESCR-carbaS), while 4.3% were also non-susceptible to carbapenems (ESCR-carbaR). ESCR-carbaS isolates were contributed by all three species, with higher proportions among isolates from inpatients (20.3%) but remarkable proportions also among those from outpatients (11.1%). Most ESCR-carbaS isolates were ESBL-positive (90.5%), and most of them were contributed by E. coli carrying bla
group 1 genes. Acquired ACBLs were less common and mostly detected in P. mirabilis. ESCR-carbaR isolates were mostly contributed by K. pneumoniae (25.1% and 7.7% among K. pneumoniae isolates from inpatients and outpatients, respectively), with bla
as the most common carbapenemase gene. Results showed an increasing trend for both ESBL and carbapenemase producers in comparison with previous Italian surveys, also among outpatients.
Proteus mirabilis, named for the Greek god who changed shape to avoid capture, has fascinated microbiologists for more than a century with its unique swarming differentiation, Dienes line formation ...and potent urease activity. Transcriptome profiling during both host infection and swarming motility, coupled with the availability of the complete genome sequence for P. mirabilis, has revealed the occurrence of interbacterial competition and killing through a type VI secretion system, and the reciprocal regulation of adhesion and motility, as well as the intimate connections between metabolism, swarming and virulence. This Review addresses some of the unique and recently described aspects of P. mirabilis biology and pathogenesis, and emphasizes the potential role of this bacterium in single-species and polymicrobial urinary tract infections.
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