Comorbidity rates of autism spectrum disorder and functional neurological disorders: A systematic review, meta-analysis of proportions and qualitative synthesis.

Autism spectrum disorder (ASD) and functional neurological disorders (FND) are relatively common conditions, and there has been recent interest in the overlap between them. Both conditions share core features of alexithymia, impaired interoception and deficits in attentional focus. To date, relatively little is known about the comorbidity rates between ASD and FND.

An extensively validated whole-cell biosensor for specific, sensitive and high-throughput detection of antibacterial inhibitors targeting cell-wall biosynthesis.

Background: Whole-cell biosensor strains are powerful tools for antibacterial drug discovery, in principle allowing the identification of inhibitors acting on specific, high-value target pathways. Whilst a variety of biosensors have been described for detecting cell-wall biosynthesis inhibitors (CWBIs), these strains typically lack specificity and/or sensitivity, and have for the most part not been rigorously evaluated as primary screening tools. Here, we describe several Staphylococcus aureus CWBI biosensors and show that specific and sensitive biosensor-based discovery of CWBIs is achievable.

A platform for detecting cross-resistance in antibacterial drug discovery.

Background: To address the growing antibiotic resistance problem, new antibacterial drugs must exert activity against pathogens resistant to agents already in use. With a view to providing a rapid means for deselecting antibacterial drug candidates that fail to meet this requirement, we report here the generation and application of a platform for detecting cross-resistance between established and novel antibacterial agents.

Methods: This first iteration of the cross-resistance platform (CRP) consists of 28 strains of defined resistance genotype, established in a uniform genetic background (the SH1000 strain of the clinically significant pathogen Staphylococcus aureus).

Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure.

Sporadic literature reports describe isolates of pathogenic bacteria that harbor an antibiotic resistance determinant but remain susceptible to the corresponding antibiotic as a consequence of a genetic defect. Such strains represent a source from which antibiotic resistance may reemerge to cause treatment failure in patients. Here, we report a systematic investigation into the prevalence and nature of this phenomenon, which we term ilencing of ntibiotic esistance by utation (SARM).

Acquired Nisin Resistance in Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module.

Resistance to the lantibiotic nisin (NIS) arises readily in as a consequence of mutations in the gene, which encodes the sensor kinase of the NsaRS two-component regulatory system. Here we present a series of studies to establish how these mutational changes result in reduced NIS susceptibility. Comparative transcriptomic analysis revealed upregulation of the NsaRS regulon in a NIS-resistant mutant of versus its otherwise-isogenic progenitor, indicating that NIS resistance mutations prompt gain-of-function in NsaS.

Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of γ-actinorhodin.

Of the thousands of natural product antibiotics discovered to date, only a handful have been developed for the treatment of bacterial infection. The clinically unexploited majority likely include compounds with untapped potential as antibacterial drugs, and in view of the ever-growing unmet medical need for such agents, warrant systematic re-evaluation. Here we revisit the actinorhodins, a class that was first reported 70 years ago, but which remains poorly characterized.

Cryptic silver resistance is prevalent and readily activated in certain Gram-negative pathogens.

Objectives: To assess the prevalence of cryptic silver (Ag+) resistance amongst clinical isolates of Gram-negative bacteria, and to examine how overt Ag+ resistance becomes activated in such strains.

Methods: Established methods were used to determine the susceptibility of 444 recent clinical isolates to Ag+, and to evaluate the potential for overt Ag+ resistance to emerge in susceptible isolates by spontaneous mutation. The genetic basis for Ag+ resistance was investigated using PCR amplification and DNA sequencing.

Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme.

Bacterial aminoacyl-tRNA synthetases (aaRSs) represent promising antibacterial drug targets. Unfortunately, the aaRS inhibitors that have to date reached clinical trials are subject to rapid resistance development through mutation, a phenomenon that limits their potential clinical utility. Here, we confirm the intuitively correct idea that simultaneous targeting of two different aaRS enzymes prevents the emergence of spontaneous bacterial resistance at high frequency, a finding that supports the development of multitargeted anti-aaRS therapies.

A Polymorphism in leuS Confers Reduced Susceptibility to GSK2251052 in a Clinical Isolate of Staphylococcus aureus.

GSK2251052 is a broad-spectrum antibacterial inhibitor of leucyl tRNA-synthetase (LeuRS) that has been evaluated in phase II clinical trials. Here, we report the identification of a clinical isolate of Staphylococcus aureus that exhibits reduced susceptibility to GSK2251052 without prior exposure to the compound and demonstrate that this phenotype is attributable to a single amino acid polymorphism (P329) within the editing domain of LeuRS.

Silver resistance in Gram-negative bacteria: a dissection of endogenous and exogenous mechanisms.

Objectives: To gain a more detailed understanding of endogenous (mutational) and exogenous (horizontally acquired) resistance to silver in Gram-negative pathogens, with an emphasis on clarifying the genetic bases for resistance.

Methods: A suite of microbiological and molecular genetic techniques was employed to select and characterize endogenous and exogenous silver resistance in several Gram-negative species.

Results: In Escherichia coli, endogenous resistance arose after 6 days of exposure to silver, a consequence of two point mutations that were both necessary and sufficient for the phenotype.

Monitoring and management of metabolic abnormalities: mixed-method evaluation of a successful intervention.

Objective: To describe the process and impact of a service-level intervention on metabolic monitoring and follow-up of patients of a mental health service who were prescribed clozapine, and describe the metabolic health of these patients.

Methods: The intervention - Let's Get Physical - involved designating two months annually as 'physical health months', during which revised service protocol required metabolic monitoring for all eligible patients. Mixed methods were used to assess rates of monitoring at baseline, during the two physical health months, and follow-up and factors influencing practice.

Design, synthesis and evaluation of second generation MurF inhibitors based on a cyanothiophene scaffold.

MurF ligase is a crucial enzyme that catalyses the ultimate intracellular step of bacterial peptidoglycan biosynthesis, and thus represents an attractive target for antibacterial drug discovery. We designed, synthesized and evaluated a new series of cyanothiophene-based inhibitors of MurF enzymes from Streptococcus pneumoniae and Escherichia coli. The target compounds had increased polarity compared to the first generation of inhibitors, with demonstrated enzyme inhibitory potencies in the low micromolar range.

Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF.

Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc-L-Ala-γ-D-Glu-meso-DAP (or L-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs.

The target of daptomycin is absent from Escherichia coli and other gram-negative pathogens.

Antistaphylococcal agents commonly lack activity against Gram-negative bacteria like Escherichia coli owing to the permeability barrier presented by the outer membrane and/or the action of efflux transporters. When these intrinsic resistance mechanisms are artificially compromised, such agents almost invariably demonstrate antibacterial activity against Gram negatives. Here we show that this is not the case for the antibiotic daptomycin, whose target appears to be absent from E.

The silver cation (Ag+): antistaphylococcal activity, mode of action and resistance studies.

Objectives: To examine several poorly understood or contentious aspects of the antibacterial activity of silver (Ag(+)), including its cidality, mode of action, the prevalence of resistance amongst clinical staphylococcal isolates and the propensity for Staphylococcus aureus to develop Ag(+) resistance.

Methods: The effects of Ag(+) on the viability, macromolecular synthesis and membrane integrity of S. aureus SH1000 were assessed using established methodology.

6-Arylpyrido[2,3-d]pyrimidines as novel ATP-competitive inhibitors of bacterial D-alanine:D-alanine ligase.

Background: ATP-dependent D-alanine:D-alanine ligase (Ddl) is a part of biochemical machinery involved in peptidoglycan biosynthesis, as it catalyzes the formation of the terminal D-ala-D-ala dipeptide of the peptidoglycan precursor UDPMurNAc-pentapeptide. Inhibition of Ddl prevents bacterial growth, which makes this enzyme an attractive and viable target in the urgent search of novel effective antimicrobial drugs. To address the problem of a relentless increase in resistance to known antimicrobial agents we focused our attention to discovery of novel ATP-competitive inhibitors of Ddl.

XF-70 and XF-73, novel antibacterial agents active against slow-growing and non-dividing cultures of Staphylococcus aureus including biofilms.

Objectives: Slow-growing and non-dividing bacteria exhibit tolerance to many antibiotics. However, membrane-active agents may act against bacteria in all growth phases. We sought to examine whether the novel porphyrin antibacterial agents XF-70 and XF-73, which have rapid membrane-perturbing activity against Staphylococcus aureus, retained antistaphylococcal activity against growth-attenuated cells.

Effect of bacterial endotoxin and middle ear effusion on ciliary activity: implications for otitis media.

Objectives/hypothesis: Otitis media with effusion (OME) is the most common cause of childhood deafness. The pathogenesis is not fully understood, especially the reasons for failure of mucociliary clearance of the middle ear. It is not clear whether the cilia function normally in the middle ear and eustachian tube in the chronic phase of otitis media with effusion.