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Drugs Jun 2024Cefepime/enmetazobactam (EXBLIFEP), an intravenous (IV) antibacterial fixed-dose combination of a 4th generation cephalosporin and an extended-spectrum β-lactamase... (Review)
Review
Cefepime/enmetazobactam (EXBLIFEP), an intravenous (IV) antibacterial fixed-dose combination of a 4th generation cephalosporin and an extended-spectrum β-lactamase (ESBL) inhibitor, is being developed by Allecra Therapeutics and ADVANZ PHARMA for the treatment of infections caused by multi-drug-resistant (MDR) Gram-negative bacteria. In February 2024, cefepime/enmetazobactam was approved in the USA for use in adults with complicated urinary tract infections (cUTI) including pyelonephritis, caused by susceptible strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex. In March 2024, cefepime/enmetazobactam was approved in the EU for use in adults for the treatment of cUTI, including pyelonephritis, and hospital-acquired pneumonia, including ventilator associated pneumonia, and the treatment of patients with bacteraemia occurring in association with or suspected to be associated with any of these infections. This article summarizes the milestones in the development of cefepime/enmetazobactam leading to this first approval for the treatment of adults with infections caused by MDR Gram-negative bacteria.
Topics: Humans; Cefepime; Anti-Bacterial Agents; Urinary Tract Infections; Drug Approval; Gram-Negative Bacterial Infections; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Cephalosporins; beta-Lactamase Inhibitors; United States; Drug Combinations; Pyelonephritis
PubMed: 38761353
DOI: 10.1007/s40265-024-02035-2 -
MSystems Aug 2023is a Gram-negative bacterium recognized for its unique swarming motility and urease activity. A previous proteomic report on four strains hypothesized that, unlike...
is a Gram-negative bacterium recognized for its unique swarming motility and urease activity. A previous proteomic report on four strains hypothesized that, unlike other Gram-negative bacteria, may not exhibit significant intraspecies variation in gene content. However, there has not been a comprehensive analysis of large numbers of genomes from various sources to support or refute this hypothesis. We performed comparative genomic analysis on 2,060 genomes. We sequenced the genomes of 893 isolates recovered from clinical specimens from three large US academic medical centers, combined with 1,006 genomes from NCBI Assembly and 161 genomes assembled from Illumina reads in the public domain. We used average nucleotide identity (ANI) to delineate species and subspecies, core genome phylogenetic analysis to identify clusters of highly related genomes, and pan-genome annotation to identify genes of interest not present in the model strain HI4320. Within our cohort, is composed of 10 named species and 5 uncharacterized genomospecies. can be subdivided into three subspecies; subspecies 1 represented 96.7% (1,822/1,883) of all genomes. The pan-genome includes 15,399 genes outside of HI4320, and 34.3% (5,282/15,399) of these genes have no putative assigned function. Subspecies 1 is composed of several highly related clonal groups. Prophages and gene clusters encoding putatively extracellular-facing proteins are associated with clonal groups. Uncharacterized genes not present in the model strain HI4320 but with homology to known virulence-associated operons can be identified within the pan-genome. IMPORTANCE Gram-negative bacteria use a variety of extracellular facing factors to interact with eukaryotic hosts. Due to intraspecies genetic variability, these factors may not be present in the model strain for a given organism, potentially providing incomplete understanding of host-microbial interactions. In contrast to previous reports on , but similar to other Gram-negative bacteria, has a mosaic genome with a linkage between phylogenetic position and accessory genome content. encodes a variety of genes that may impact host-microbe dynamics beyond what is represented in the model strain HI4320. The diverse, whole-genome characterized strain bank from this work can be used in conjunction with reverse genetic and infection models to better understand the impact of accessory genome content on bacterial physiology and pathogenesis of infection.
Topics: Humans; Proteus mirabilis; Proteomics; Phylogeny; Virulence; Virulence Factors
PubMed: 37341494
DOI: 10.1128/msystems.00159-23 -
Clinical Microbiology and Infection :... Sep 2023To analyse carbapenemases in Proteus mirabilis and assess the performance of carbapenemase detection assays.
OBJECTIVES
To analyse carbapenemases in Proteus mirabilis and assess the performance of carbapenemase detection assays.
METHODS
Eighty-one clinical P. mirabilis isolates with high-level resistance at least to ampicillin (>32 mg/L) or previous detection of carbapenemases were selected and investigated by three susceptibility testing methods (microdilution, automated susceptibility testing, and disk diffusion), six phenotypic carbapenemase assays (CARBA NP, modified carbapenemase inactivation method [CIM], modified zinc-supplemented CIM, simplified CIM, faropenem, and carbapenem-containing agar), two immunochromatographic assays, and whole-genome sequencing.
RESULTS
Carbapenemases were detected in 43 of 81 isolates (OXA-48-like [n = 13]; OXA-23 [n = 12]; OXA-58 [n = 12]; New Delhi metallo-β-lactamase (NDM) [n = 2]; Verona integron-encoded metallo-β-lactamase (VIM) [n = 2]; Imipenemase (IMP) [n = 1]; Klebsiella pneumoniae carbapenemase (KPC) [n = 1]). Carbapenemase-producing Proteus were frequently susceptible to ertapenem (26/43; 60%), meropenem (28/43; 65%), ceftazidime (33/43; 77%), and some even to piperacillin-tazobactam (9/43; 21%). Sensitivity/specificity of phenotypic tests were 30% (CI: 17-46%)/89% (CI: 75-97%) for CARBA NP, 74% (CI: 60-85%)/82% (CI: 67-91%) for faropenem, 91% (CI: 78-97%)/82% (CI: 66-92%) for simplified CIM, and 93% (CI: 81-99%)/100% (CI: 91-100%) for modified zinc-supplemented CIM. An algorithm for improved detection was developed, which demonstrated sensitivity/specificity of 100% (CI: 92-100%)/100% (CI: 91-100%) on the 81 isolates, and 100% (CI: 29-100%)/100% (CI: 96-100%) in a prospective analysis of additional 91 isolates. Interestingly, several OXA-23-producing isolates belonged to the same clonal lineage reported previously from France.
DISCUSSION
Current susceptibility testing methods and phenotypic tests frequently fail to detect carbapenemases in P. mirabilis, which could result in inadequate antibiotic treatment. In addition, the non-inclusion of bla in many molecular carbapenemase assays further impedes their detection. Therefore, the prevalence of carbapenemases in P. mirabilis is likely underestimated. With the herein proposed algorithm, carbapenemase-producing Proteus can be easily identified.
Topics: Humans; Proteus mirabilis; Bacterial Proteins; beta-Lactamases; Anti-Bacterial Agents; Algorithms; Zinc; Microbial Sensitivity Tests
PubMed: 37271195
DOI: 10.1016/j.cmi.2023.05.032 -
Ecotoxicology and Environmental Safety Jun 2024Cadmium (Cd) pollution is a serious global environmental problem, which requires a global concern and practical solutions. Microbial remediation has received widespread...
Cadmium (Cd) pollution is a serious global environmental problem, which requires a global concern and practical solutions. Microbial remediation has received widespread attention owing to advantages, such as environmental friendliness and soil amelioration. However, Cd toxicity also severely deteriorates the remediation performance of functional microorganisms. Analyzing the mechanism of bacterial resistance to Cd stress will be beneficial for the application of Cd remediation. In this study, the bacteria strain, up to 1400 mg/L Cd resistance, was employed and identified as Proteus mirabilis Ch8 (Ch8) through whole genome sequence analyses. The results indicated that the multiple pathways of immobilizing and detoxifying Cd maintained the growth of Ch8 under Cd stress, which also possessed high Cd extracellular adsorption. Firstly, the changes in surface morphology and functional groups of Ch8 cells were observed under different Cd conditions through SEM-EDS and FTIR analyses. Under 100 mg/L Cd, Ch8 cells exhibited aggregation and less flagella; the Cd biosorption of Ch8 was predominately by secreting exopolysaccharides (EPS) and no significant change of functional groups. Under 500 mg/L Cd, Ch8 were present irregular polymers on the cell surface, some cells with wrapping around; the Cd biosorption capacity exhibited outstanding effects (38.80 mg/g), which was mainly immobilizing Cd by secreting and interacting with EPS. Then, Ch8 also significantly enhanced the antioxidant enzyme activity and the antioxidant substance content under different Cd conditions. The activities of SOD and CAT, GSH content of Ch8 under 500 mg/L Cd were significantly increased by 245.47%, 179.52%, and 241.81%, compared to normal condition. Additionally, Ch8 significantly induced the expression of Acr A and Tol C (the resistance-nodulation-division (RND) efflux pump), and some antioxidant genes (SodB, SodC, and Tpx) to reduce Cd damage. In particular, the markedly higher expression levels of SodB under Cd stress. The mechanism of Ch8 lays a foundation for its application in solving soil remediation.
Topics: Proteus mirabilis; Cadmium; Soil Pollutants; Biodegradation, Environmental
PubMed: 38728947
DOI: 10.1016/j.ecoenv.2024.116432 -
BMC Microbiology Aug 2023Proteus mirabilis, a naturally resistant zoonotic bacterium belonging to the Enterobacteriaceae family, has exhibited an alarming increase in drug resistance....
Proteus mirabilis, a naturally resistant zoonotic bacterium belonging to the Enterobacteriaceae family, has exhibited an alarming increase in drug resistance. Consequently, there is an urgent need to explore alternative antimicrobial agents. Bacteriophages, viruses that selectively target bacteria, are abundant in the natural environment and have demonstrated potential as a promising alternative to antibiotics. In this study, we successfully isolated four strains of Proteus mirabilis phages from sewage obtained from a chicken farm in Sichuan, China. Subsequently, we characterized one of the most potent lytic phages, Q29, by examining its biological and genomic features. Comparative genomic analysis revealed the functional genes and phylogenetic evolution of Q29 phages. Our findings revealed that Proteus mirabilis bacteriophage Q29 possesses an icosahedral symmetrical head with a diameter of 95 nm and a tail length of 240 nm. Moreover, phage Q29 exhibited stability within a temperature range of 37 ℃ to 55 ℃ and under pH conditions ranging from 4 to 9. The optimal multiplicity of infection (MOI) for this phage was determined to be 0.001. Furthermore, the one-step growth curve results indicated an incubation period of approximately 15 min, an outbreak period of approximately 35 min, and an average cleavage quantity of approximately 60 plaque-forming units (PFU) per cell. The genome of phage Q29 was found to have a total length of 58,664 base pairs and encoded 335 open reading frames (ORFs) without carrying any antibiotic resistance genes. Additionally, genetic evolutionary analysis classified phage Q29 within the family Caudalidae and the genus Myotail. This study provides valuable research material for further development of Proteus mirabilis bacteriophage biologics as promising alternatives to antibiotics, particularly in light of the growing challenge of antibiotic resistance posed by this bacterium.
Topics: Bacteriophages; Proteus mirabilis; Phylogeny; Genomics; Anti-Bacterial Agents; Genome, Viral
PubMed: 37553593
DOI: 10.1186/s12866-023-02960-4 -
International Journal of Molecular... Nov 2023, an opportunistic pathogen of the urinary tract, is known for its dimorphism and mobility. A connection of lipid alterations, induced by the rods elongation process,...
, an opportunistic pathogen of the urinary tract, is known for its dimorphism and mobility. A connection of lipid alterations, induced by the rods elongation process, with enhanced pathogenicity of long-form morphotype for the development of urinary tract infections, seems highly probable. Therefore, research on the adjustment in the composition and organization of lipids forming elongated rods was undertaken. The analyses performed using the ultra-high performance liquid chromatography with tandem mass spectrometry showed that drastic modifications in the morphology of rods that occur during the swarming process are directly related to deprivation of the long-form cells of PE 33:1 and PG 31:2 and their enrichment with PE 32:1, PE 34:1, PE 34:2, PG 30:2, PG 32:1, and PG 34:1. The analyses conducted by the gas chromatography-mass spectrometry showed negligible effects of the swarming process on fatty acids synthesis. However, the constant proportions between unsaturated and saturated fatty acids confirmed that phenotypic modifications in the rods induced by motility were independent of the saturation of the phospholipid tails. The method of the Förster resonance energy transfer revealed the influence of the swarming process on the melting of ordered lipid rafts present in the short-form rods, corresponding to the homogeneity of lipid bilayers in the long-form rods of . Confocal microscope photographs visualized strong Rhod-PE fluorescence of the whole area of swarmer cells, in contrast to weak membrane fluorescence of non-swarmer cells. It suggested an increased permeability of the bilayers in long-form rods morphologically adapted to the swarming process. These studies clearly demonstrate that swarming motility regulates the lipid composition and organization in rods.
Topics: Humans; Proteus mirabilis; Urinary Tract; Urinary Tract Infections; Chemical Phenomena; Lipids; Proteus Infections
PubMed: 38003652
DOI: 10.3390/ijms242216461