Antibacterial evaluation of synthetic thiazole compounds in vitro and in vivo in a methicillin-resistant staphylococcus aureus (MRSA) skin infection mouse model

The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), including strains resistant to current antibiotics, has contributed to an increase in the number of skin infections reported in humans in recent years. New therapeutic options are needed to counter this public health challenge. The aim of the present study was to examine the potential of thiazole compounds synthesized by our research group to be used topically to treat MRSA skin and wound infections. The broth microdilution method confirmed that the lead thiazole compound and four analogues are capable of inhibiting MRSA growth at concentrations as low as 1.3 μg/mL. Additionally, three compounds exhibited a synergistic relationship when combined with the topical antibiotic mupirocin against MRSA in vitro via the checkerboard assay. Thus the thiazole compounds have potential to be used alone or in combination with mupirocin against MRSA. When tested against human keratinocytes, four derivatives of the lead compound demonstrated an improved toxicity profile (were found to be non-toxic up to a concentration of 20 μg/mL). Utilizing a murine skin infection model, we confirmed that the lead compound and three analogues exhibited potent antimicrobial activity in vivo, with similar capability as the antibiotic mupirocin, as they reduced the burden of MRSA present in skin wounds by more than 90%. Taken altogether, the present study provides important evidence that these thiazole compounds warrant further investigation for development as novel topical antimicrobials to treat MRSA skin infections. © 2015 Mohammad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Serum oxytocin levels in adolescents with conduct disorder associated with callous-unemotional traits

Abstract Background Conduct disorder (CD) is a serious and common psychiatric disorder affecting children and adolescents. “Callous-unemotional traits” is a new specifier added to the diagnosis of CD in the DSM-5. The new specifier is thought to be associated with more severity and higher genetic load. Oxytocin is known to be related to interpersonal sympathy and social affection, and so its deficiency might be related to unemotionality. This work aims to explore the levels of serum oxytocin in adolescents with CD associated with callous-unemotional (CU) traits as compared to healthy control subjects. Twenty patients aged 12–18 years and 20 controls of the same age range were recruited. An Arabic-translated and validated version of Mini International Neuropsychiatric Interview for kids (MINI-kid) was used to confirm the diagnosis. The Youth Psychopathic Inventory-short version (YPI-short version) and the Inventory of Callous-Unemotional Traits (ICU), both parent and self-reports, were all translated into Arabic and validated by the authors and used to evaluate the sample. Evaluation of serum oxytocin level using ELISA technique was done. Results After statistical adjustment for differences in socioeconomic status, an adolescent with CD associated with CU traits showed low levels of serum oxytocin level as compared with the control group. Serum oxytocin levels were negatively correlated in a statistically significant degree with the unemotional, the callousness, and the uncaring subscores of ICU—self-report. Conclusions Low levels of serum oxytocin might play a potential role as a biomarker for CU traits and CD severity in adolescents with CD

Psychometric properties and cross-cultural comparison of the Arabic version of the Child Behavior Checklist (CBCL), Youth Self Report (YSR), and Teacher’s Report Form (TRF) in a sample of Egyptian children

Abstract Background The Achenbach System of Empirically Based Assessment (ASEBA) forms are among the most studied instruments for assessing behavioral, emotional, social, and thought problems in children and adolescents worldwide. Although ASEBA instruments have been translated into Arabic, fewer studies have investigated their psychometric properties and norms in Arabic speaking societies than in other societies. Methods Revisions were made to the Modern Standard Arabic (MSA) translations of the Child Behavior Checklist for Ages 6–18 (CBCL/6–18), the Teacher’s Report Form (TRF), and the Youth Self-Report (YSR). Parents of 6–18-year-olds who came to the general pediatric clinic in Tanta University Hospital during a 2-year period for routine check-ups were invited to fill out the CBCL/6–18 (N = 595), while 11–18-year-olds were invited to fill out the YSR (N = 409). TRFs were filled out by teachers (N = 329). Results Confirmatory factor analyses supported the previously reported eight-factor syndrome structure of the forms with good psychometric properties and moderate cross-informant correlations. The mean CBCL/6–18 and YSR Total Problem scores qualified for the previously established ASEBA Multicultural Norm Group 2, while the mean TRF Total Problem score qualified for group 3. Conclusions The good psychometric properties and the identification of Multicultural Norm Groups for scores obtained with the Arabic translations of ASEBA forms in Egyptian society support use of the ASEBA for assessment and outcome evaluations of behavioral, emotional, social, and thought problems among Egyptian youth

Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties

A series of second-generation analogues for 2-(1-(2-(4-butyl­phenyl)-4-methyl­thiazol-5-yl)­ethylidene)­amino­guanidine (<b>1</b>) have been synthesized and tested against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue <b>17</b> was identified as the most potent analogue constructed thus far. The corresponding amine <b>8</b> was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the <i>n</i>-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue <b>29</b>, which showed significant improvement in <i>in vitro</i> anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound <b>17</b> demonstrated a superior <i>in vitro</i> and <i>in vivo</i> pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis

Discovery and Characterization of Potent Thiazoles versus Methicillin- and Vancomycin-Resistant <i>Staphylococcus aureus</i>

Methicillin- and vancomycin-resistant <i>Staphylococcus aureus</i> (MRSA and VRSA) infections are growing global health concerns. Structure–activity relationships of phenylthiazoles as a new antimicrobial class have been addressed. We present 10 thiazole derivatives that exhibit strong activity against 18 clinical strains of MRSA and VRSA with acceptable PK profile. Three derivatives revealed an advantage over vancomycin by rapidly eliminating MRSA growth within 6 h, and no derivatives are toxic to HeLa cells at 11 μg/mL

Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis

The promising antibacterial potency of arylthiazole antibiotics is offset by their limited activity against intracellular bacteria (namely methicillin-resistant Staphylococcus aureus (MRSA)), similar to many clinically-approved antibiotics. The failure to target these hidden pathogens is due to the compounds' lack of proper characteristics to accumulate intracellularly. Fine tuning of the size and polar-surface-area of the linking heteroaromatic ring provided a new series of 5-thiazolylarylthiazoles with balanced properties that allow them to sufficiently cross and accumulate inside macrophages infected with MRSA. The most promising compound 4i exhibited rapid bactericidal activity, good metabolic stability and produced over 80% reduction of intracellular MRSA in infected macrophages

Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of <i>Candida</i>, <i>Cryptococcus</i>, and <i>Aspergillus</i>. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (<b>4b</b>) with broad-spectrum antifungal activity that inhibits the growth of pertinent species of <i>Candida</i> (chiefly <i>C. albicans</i>), <i>Cryptococcus</i>, and <i>Aspergillus</i> at a concentration of as low as 0.5 μg/mL. Furthermore, <b>4b</b>, at a subinhibitory concentration, interfered with the expression of two key virulence factors (hyphae and biofilm formation) involved in <i>C. albicans</i> pathogenesis. Three yeast deletion strains (<i>cox17</i>Δ, <i>ssa1</i>Δ, and <i>aft2</i>Δ) related to metal ion homeostasis were found to be highly sensitive to <b>4b</b> in growth assays, indicating that the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to <b>4b</b>, further corroborating that the compound targets metal ion homeostasis. <b>4b</b>’s potent antifungal activity was validated in vivo, as the compound enhanced the survival of <i>Caenorhabditis elegans</i> infected with fluconazole-resistant <i>C. albicans</i>. The present study indicates that <b>4b</b> warrants further investigation as a novel antifungal agent