Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylateinhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents

Eleven-Year Surveillance of Methicillin-Resistant Staphylococcus aureus Infections at an Academic Health Centre

Introduction. Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen associated with nosocomial and community infections. There is a continual focus on the epidemiology of this public health threat owing to the increase in its spread and rapid development of resistance. Aim. We aimed to describe the clinical presentations of MRSA infections at an academic health centre by demonstrating the time trend of antibiotic resistance. Methodology. We retrospectively reviewed cases during an 11-year period (from January 2009 to December 2019) with positive cultures for MRSA from various clinical sites in King Fahad Hospital of the University, to understand their clinical and microbiological profiles. Screening and colonisation samples were excluded. Results. A total of 1338 MRSA isolates were identified, with an increasing trend from 5.2% to 14.5% during 2009–2019. Skin and soft tissue samples were the most common source (52.4%) of MRSA infections. Vancomycin activity remained stable against MRSA, and only one isolate showed resistance to linezolid (<1%). A significant reduction in susceptibility to clindamycin (p = 0.003), trimethoprim-sulfamethoxazole (p = 0.001), and rifampin (p <0.0001) was detected over the study period. Conclusion. MRSA infections still represent a significant burden on healthcare systems. Our data support the need for constant local and regional surveillance to devise relevant protocols to manage MRSA infections. Empirical therapy needs to consider the changing antimicrobial susceptibility trends among MRSA isolates

Interplays between copper and Mycobacterium tuberculosis GroEL1

The recalcitrance of pathogenic Mycobacterium tuberculosis, the agent of tuberculosis, to eradication is due to various factors allowing bacteria to escape from stress situations. The mycobacterial chaperone GroEL1, overproduced after macrophage entry and under oxidative stress, could be one of these key players. We previously reported that GroEL1 is necessary for the biosynthesis of phthiocerol dimycocerosate, a virulence-associated lipid and for reducing antibiotic susceptibility. In the present study, we showed that GroEL1, bearing a unique C-terminal histidine-rich region, is required for copper tolerance during Mycobacterium bovis BCG biofilm growth. Mass spectrometry analysis demonstrated that GroEL1 displays high affinity for copper ions, especially at its C-terminal histidine-rich region. Furthermore, the binding of copper protects GroEL1 from destabilization and increases GroEL1 ATPase activity. Altogether, these findings suggest that GroEL1 could counteract copper toxicity, notably in the macrophage phagosome, and further emphasizes that M. tuberculosis GroEL1 could be an interesting antitubercular target

A Protocol for Diagnosis and Management of Cerebrospinal Shunt Infections and other Infectious Conditions in Neurosurgical Practice

Infections of the cerebrospinal shunts and other neurosurgical structures are not uncommon in the clinical practice. These infections are mostly clinical emergencies carrying negative prognostic impacts on the patients as well as consuming healthcare resources. The low pathogenicity nature of some implicated pathogens results in minimal physical signs that may complicate the diagnosis and mislead the practitioner. Furthermore, little good prospective data exists in the field of neurosurgical infections and most available evidence is derived from retrospective nonrandomized studies. This protocol is meant to utilize the available evidence-based best practice to provide a guide for diagnosing and managing common neurosurgical infections including those associated with cerebrospinal shunts. The effective management of these neurosurgical infections requires a good collaboration between the clinical team, clinical pharmacist and clinical microbiologist

Antimicrobial Resistance in Ventilator-Associated Pneumonia: Predictive Microbiology and Evidence-Based Therapy

Abstract Ventilator-associated pneumonia (VAP) is a serious intensive care unit (ICU)-related infection in mechanically ventilated patients that is frequent, as more than half of antibiotics prescriptions in ICU are due to VAP. Various risk factors and diagnostic criteria for VAP have been referred to in different settings. The estimated attributable mortality of VAP can go up to 50%, which is higher in cases of antimicrobial-resistant VAP. When the diagnosis of pneumonia in a mechanically ventilated patient is made, initiation of effective antimicrobial therapy must be prompt. Microbiological diagnosis of VAP is required to optimize timely therapy since effective early treatment is fundamental for better outcomes, with controversy continuing regarding optimal sampling and testing. Understanding the role of antimicrobial resistance in the context of VAP is crucial in the era of continuously evolving antimicrobial-resistant clones that represent an urgent threat to global health. This review is focused on the risk factors for antimicrobial resistance in adult VAP and its novel microbiological tools. It aims to summarize the current evidence-based knowledge about the mechanisms of resistance in VAP caused by multidrug-resistant bacteria in clinical settings with focus on Gram-negative pathogens. It highlights the evidence-based antimicrobial management and prevention of drug-resistant VAP. It also addresses emerging concepts related to predictive microbiology in VAP and sheds lights on VAP in the context of coronavirus disease 2019 (COVID-19)

A case of bacteremia caused by Campylobacter fetus: an unusual presentation in an infant

Amani M Alnimr Department of Microbiology, King Fahad University Hospital, College of Medicine, University of Dammam, Saudi Arabia Abstract: Bacteremia due to Campylobacter spp. is rarely reported, and Campylobacter fetus is the species most commonly exhibiting vascular tropism, as occurred in this case report describing the diagnosis of C. fetus bacteremia in an infant presenting with respiratory tract infection. A 5-month-old baby, with undiagnosed failure to thrive, presented to the acute care service with a high fever and respiratory symptoms of 2 days duration. The initial clinical and laboratory diagnosis suggested bacteremia, but there was difficulty with recovery and identification of the organism from blood. Subsequent laboratory testing confirmed C. fetus as the etiological agent. Campylobacter isolated from blood culture bottles may give atypical laboratory features, rendering its identification challenging. Thus, such an infrequent species might be underestimated in frequency, and it should be considered in diagnostic laboratories, when a gram-negative organism with atypical findings is encountered in respiratory samples or blood culture bottles. Keywords: microbiology, vascular tropism, blood stream infectio

Diagnostic performance of isothermal strand displacement amplification of Mycobacterium tuberculosis IS 6110 in tissue samples

AbstractBackgroundVisualized histopathological findings in tissue samples are not specific for tuberculosis while mycobacterial cultures from such specimens have low yields and long turn around times. A rapid, sensitive method is therefore needed for detection of Mycobacterium tuberculosis in paucibacillary tissue samples.MethodologyIn this paper, a total of 158 tissue specimens, including 42 culture-positives, were tested for the presence of Mycobacterium tuberculosis by strand displacement amplification of DNA targeting the region of the insertion element IS 6110 and detected by a chemiluminescence based commercial platform (BDProbeTec™ ET System). The amplification results were correlated to histopathology, microscopy and microbiological culture.ResultsThe strand displacement amplification based assay showed low overall sensitivity (31.5%) but high specificity (97.5%) which varied across various tissue types. Only 35.7% of culture-positive biopsies were positive by the molecular assay. Some discrepancy were attributed to suboptimal performance of the traditional methods.ConclusionsThe assay is useful to rule in the disease in common tissue specimens (lung, pleura and lymph node); but less so in other tissue types. The poor sensitivity in tissue specimens necessitates careful interpretation of data generated by the assay in conjunction with a clinical suspicion of tuberculosis for making decision regarding empirical treatment. The complexity of the disease pathology along with the low bacillary load and clumping tendency require selection of more sensitive methods or gene targets