Rapid Molecular Diagnostics to Inform Empiric Use of Ceftazidime/Avibactam and Ceftolozane/Tazobactam Against Pseudomonas aeruginosa: PRIMERS IV.

Background: Overcoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa.

β-Defensins Coordinate In Vivo to Inhibit Bacterial Infections of the Trachea.

β-defensins are predicted to play an important role in innate immunity against bacterial infections in the airway. We previously observed that a type III-secretion product of inhibits the NF-κB-mediated induction of a β-defensin in airway epithelial cells in vitro. To confirm this in vivo and to examine the relative roles of other β-defensins in the airway, we infected wild-type C57BL/6 mice and mice with a deletion of the mBD-1 gene with wild-type strain, RB50 and its mutant strain lacking the type III-secretion system, WD3.

Coidentification of and in a Clinical Enterobacter cloacae Isolate from China.

We describe the first report of a clinical colistin-resistant ST84 isolate coharboring (previously named ) and from a patient in China. The -harboring IncX3 plasmid and the novel -harboring ColE plasmid were completely sequenced. Although this isolate showed a high level of resistance to colistin, plasmid transformation, gene subcloning, susceptibility testing, and lipid A matrix-assisted laser desorption ionization mass spectrometry analysis indicated that itself does not confer resistance to colistin.

Two for the price of one: emerging carbapenemases in a returning traveller to New York City.

We report a case of a complex orthopaedic infection in a patient returning to New York City from Bangladesh where he was involved in a serious motor vehicle accident. He developed extensive osteomyelitis with a carbapenem-resistant The isolate was unique due to the coexistence of New Delhi metallo-β-lactamase-1 and Oxacillinase type-181 carbapenemases, which are relatively uncommon in North America and were presumably acquired in Bangladesh. Herein, we explore challenges associated with management of carbapenem-resistant Enterobacteriaceae infections, including limited available data on effective antimicrobial therapy.

Emergence of Resistance to Colistin During the Treatment of Bloodstream Infection Caused by Carbapenemase-Producing .

We report the emergence of colistin resistance in carbapenemase (KPC)-producing after 8 days of colistin-based therapy, resulting in relapse of bloodstream infection and death. Disruption of the gene by insertion of a mobile genetic element was found to be the mechanism, which was replicated in vitro after exposure to subinhibitory concentrations of colistin and meropenem.

Mycobacterial extracellular vesicles and host pathogen interactions.

Mycobacteria, like other bacteria, archaea and eukaryotic cells, naturally release extracellular vesicles (EVs) to interact with their environment. EVs produced by pathogenic bacteria are involved in many activities including cell-cell communication, immunomodulation, virulence and cell survival. Although EVs released by thick cell wall microorganisms like mycobacteria were recognized only recently, studies of Mycobacterium tuberculosis EVs already point to their important roles in host pathogen interactions, opening exciting new areas of investigation.

ClpC and MecA, components of a proteolytic machine, prevent Spo0A-P-dependent transcription without degradation.

In Bacillus subtilis, a proteolytic machine composed of MecA, ClpC and ClpP degrades the transcription factor ComK, controlling its accumulation during growth. MecA also inhibits sporulation and biofilm formation by down-regulating spoIIG and sinI, genes that are dependent for their transcription on the phosphorylated protein Spo0A-P. Additionally, MecA has been shown to interact in vitro with Spo0A.

Trypanosoma cruzi Produces the Specialized Proresolving Mediators Resolvin D1, Resolvin D5, and Resolvin E2.

is a protozoan parasite that causes Chagas disease (CD). CD is a persistent, lifelong infection affecting many organs, most notably the heart, where it may result in acute myocarditis and chronic cardiomyopathy. The pathological features include myocardial inflammation and fibrosis.

Role of the inositol pyrophosphate multikinase Kcs1 in Cryptococcus inositol metabolism.

Cryptococcus neoformans is the most common cause of deadly fungal meningitis. This fungus has a complex inositol acquisition and utilization system, and our previous studies have shown the importance of inositol utilization in cryptococcal development and virulence. However, how inositol utilization is regulated in this fungus remains unknown.

Identification of Novel Structural Determinants in MW965 Env That Regulate the Neutralization Phenotype and Conformational Masking Potential of Primary HIV-1 Isolates.

The subtype C HIV-1 isolate MW965.26 is a highly neutralization-sensitive tier 1a primary isolate that is widely used in vaccine studies, but the basis for the sensitive neutralization phenotype of this isolate is not known. Substituting the MW965.

Carbapenem-Resistant Enterobacteriaceae Infections in Patients on Renal Replacement Therapy.

Background: Patients on chronic intermittent renal replacement therapy (RRT) are at risk for infection with carbapenem-resistant Enterobacteriaceae (CRE). However, the impact of RRT on outcomes after CRE infections remains to be defined. Here we perform a comparison of outcomes for CRE-infected patients with preserved renal function compared with CRE-infected patients on RRT.

Carbapenemase-2 (KPC-2), Substitutions at Ambler Position Asp179, and Resistance to Ceftazidime-Avibactam: Unique Antibiotic-Resistant Phenotypes Emerge from β-Lactamase Protein Engineering.

The emergence of carbapenemases (KPCs), β-lactamases that inactivate "last-line" antibiotics such as imipenem, represents a major challenge to contemporary antibiotic therapies. The combination of ceftazidime (CAZ) and avibactam (AVI), a potent β-lactamase inhibitor, represents an attempt to overcome this formidable threat and to restore the efficacy of the antibiotic against Gram-negative bacteria bearing KPCs. CAZ-AVI-resistant clinical strains expressing KPC variants with substitutions in the Ω-loop are emerging.

Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis.

Mycobacterium tuberculosis (Mtb) is a global health threat, compounded by the emergence of drug-resistant strains. A hallmark of pulmonary tuberculosis (TB) is the formation of hypoxic necrotic granulomas, which upon disintegration, release infectious Mtb. Furthermore, hypoxic necrotic granulomas are associated with increased disease severity and provide a niche for drug-resistant Mtb.

Viscous drag on the flagellum activates Bacillus subtilis entry into the K-state.

Bacillus subtilis flagella are not only required for locomotion but also act as sensors that monitor environmental changes. Although how the signal transmission takes place is poorly understood, it has been shown that flagella play an important role in surface sensing by transmitting a mechanical signal to control the DegS-DegU two-component system. Here we report a role for flagella in the regulation of the K-state, which enables transformability and antibiotic tolerance (persistence).

Asymmetric Structure of the Dimerization Domain of PhoR, a Sensor Kinase Important for the Virulence of .

The PhoP-PhoR two-component system is essential for the virulence of () and therefore represents a potential target for developing novel antituberculosis therapies. However, little is known about the mechanism by which this two-component system regulates the virulence. In this study, we demonstrated that a mutant strain has phenotypes similar to those of a mutant, suggesting that PhoP and PhoR work in the same pathway to regulate virulence.

BCG - old workhorse, new skills.

Bacille Calmette-Guérin (BCG), the only tuberculosis (TB) vaccine in clinical practice, has limitations in efficacy, immunogenicity and safety. Much current TB vaccine research focuses on engineering live mycobacteria to interfere with phagosome biology and host intracellular pathways including apoptosis and autophagy, with candidates such as BCG Δzmp1, BCG ΔureC::hly, BCG::ESX-1, Mtb ΔphoP ΔfadD26, Mtb ΔRD1 ΔpanCD and M. smegmatis Δesx-3::esx-3(Mtb) in the development pipeline.

Continued expansion of USA300-like methicillin-resistant Staphylococcus aureus (MRSA) among hospitalized patients in the United States.

We characterized spa types, SCCmec types, and antimicrobial resistance patterns of 516 methicillin-resistant Staphylococcus aureus (MRSA) isolates, collected between 2011 and 2014 from nares and blood cultures of United States patients. Among nares isolates, 45 spa types were observed; 29.9% were t002/SCCmec II and 30.

Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis.

Nitric oxide contributes to protection from tuberculosis. It is generally assumed that this protection is due to direct inhibition of Mycobacterium tuberculosis growth, which prevents subsequent pathological inflammation. In contrast, we report that nitric oxide primarily protects mice by repressing an interleukin-1- and 12/15-lipoxygenase-dependent neutrophil recruitment cascade that promotes bacterial replication.

Strains of Mycobacterium tuberculosis transmitting infection in Brazilian households and those associated with community transmission of tuberculosis.

Molecular epidemiologic studies have shown that the dynamics of tuberculosis transmission varies geographically. We sought to determine which strains of Mycobacterium tuberculosis (MTB) were infecting household contacts (HHC), and which were causing clusters of tuberculosis (TB) disease in Vitoria-ES, Brazil. A total of 741 households contacts (445 TST +) and 139 index cases were characterized according to the proportion of contacts in each household that had a tuberculin skin test positive: low (LT) (≤40% TST+), high (HT) (≥70% TST+) and (40-70% TST+) intermediate (IT) transmission.

Regulation, Function, and Detection of Protein Acetylation in Bacteria.

-Lysine acetylation is now recognized as an abundant posttranslational modification (PTM) that influences many essential biological pathways. Advancements in mass spectrometry-based proteomics have led to the discovery that bacteria contain hundreds of acetylated proteins, contrary to the prior notion of acetylation events being rare in bacteria. Although the mechanisms that regulate protein acetylation are still not fully defined, it is understood that this modification is finely tuned via both enzymatic and nonenzymatic mechanisms.

flips its lid - membrane phospholipid asymmetry modulates antifungal drug resistance and virulence.

Human fungal infections are increasing in prevalence and acquisition of antifungal drug resistance, while our antifungal drug armamentarium remains very limited, constituting a significant public health problem. Despite the fact that prominent antifungal drugs target the fungal cell membrane, very little is known about how fungal membrane biology regulates drug-target interactions. Asymmetrical phospholipid distribution is an essential property of biological membranes, which is maintained by a group of transporters that dynamically translocate specific phospholipid groups across the membrane bilayer.

Leading Antibacterial Laboratory Research by Integrating Conventional and Innovative Approaches: The Laboratory Center of the Antibacterial Resistance Leadership Group.

The Antibacterial Resistance Leadership Group (ARLG) Laboratory Center (LC) leads the evaluation, development, and implementation of laboratory-based research by providing scientific leadership and supporting standard/specialized laboratory services. The LC has developed a physical biorepository and a virtual biorepository. The physical biorepository contains bacterial isolates from ARLG-funded studies located in a centralized laboratory and they are available to ARLG investigators.

The RicAFT (YmcA-YlbF-YaaT) complex carries two [4Fe-4S] clusters and may respond to redox changes.

During times of environmental insult, Bacillus subtilis undergoes developmental changes leading to biofilm formation, sporulation and competence. Each of these states is regulated in part by the phosphorylated form of the master response regulator Spo0A (Spo0A∼P). The phosphorylation state of Spo0A is controlled by a multi-component phosphorelay.

Endocrine and Metabolic Aspects of Tuberculosis.

Endocrine and metabolic derangements are infrequent in patients with tuberculosis, but they are important when they occur. The basis for these abnormalities is complex. While Mycobacterium tuberculosis has been described to infect virtually every endocrine gland, the incidence of gland involvement is low, especially in the era of effective antituberculosis therapy.