Trivalent sulfonium compounds (TSCs): Tetrahydrothiophene-based amphiphiles exhibit similar antimicrobial activity to analogous ammonium-based amphiphiles.

Recent advances in the development of quaternary ammonium compounds (QACs) have focused on new structural motifs to increase bioactivity, but significantly less studied has been the change from ammonium- to sulfonium-based disinfectants. Herein, we report the synthesis of structurally analogous series of quaternary ammonium and trivalent sulfonium compounds (TSCs). The bioactivity profiles of these compounds generally mirror each other, and the antibacterial activity of sulfonium-based THT-18 was found to be comparable to the commercial disinfectant, BAC. The development of these compounds presents a new avenue for further study of disinfectants to combat the growing threat of bacterial resistance.

More QACs, more questions: Recent advances in structure activity relationships and hurdles in understanding resistance mechanisms.

Quaternary ammonium compounds (QACs) are a class of antimicrobials that have been around for over a century; nevertheless, they have found continued renewal in the structures to which they can be appended. Ranging from antimicrobial polymers to adding novel modes of action to existing antibiotics, QACs have found ongoing use due to their potent properties. However, resistance against QACs has begun to emerge, and the mechanism of resistance is still only partially understood. In this review, we aim to summarize the current state of the field and what is known about the mechanisms of resistance so that the QACs of the future can be designed to be evermore efficacious and utilized to unearth the remaining mysteries that surround bacteria's resistance to them.

Ester- and amide-containing multiQACs: Exploring multicationic soft antimicrobial agents.

Quaternary ammonium compounds (QACs) are ubiquitous antiseptics whose chemical stability is both an aid to prolonged antibacterial activity and a liability to the environment. Soft antimicrobials, such as QACs designed to decompose in relatively short times, show the promise to kill bacteria effectively but not leave a lasting footprint. We have designed and prepared 40 soft QAC compounds based on both ester and amide linkages, in a systematic study of mono-, bis-, and tris-cationic QAC species. Antimicrobial activity, red blood cell lysis, and chemical stability were assessed. Antiseptic activity was strong against a panel of six bacteria including two MRSA strains, with low micromolar activity seen in many compounds; amide analogs showed superior activity over ester analogs, with one bisQAC displaying average MIC activity of ∼1µM. For a small subset of highly bioactive compounds, hydrolysis rates in pure water as well as buffers of pH =4, 7, and 10 were tracked by LCMS, and indicated good stability for amides while rapid hydrolysis was observed for all compounds in acidic conditions.

Total Synthesis and Biological Investigation of Mindapyrroles A and B.

In the search for antibacterial compounds that can overcome drug resistant species, molecules that enact novel or polypharmacological mechanisms of action (MoA) are needed. As a preliminary foray into molecules of this background, the total synthesis of mindapyrroles A and B was undertaken leveraging a biomimetic approach. Following their synthesis, they and their monomer pyoluteorin were tested against a range of pathogenic bacteria in minimum inhibitory concentration assays to confirm their activity. These molecules were then tested for their ability to disrupt membrane potential in S. aureus. Our findings indicate that pyoluteorin acts as a protonophore but the mindapyrroles do not. This work encapsulates the first total synthesis of mindapyrrole B and the second total synthesis of mindapyrrole A in 11 % and 30 % overall yields, respectively. It also provides insights into the antibacterial properties and different MoAs between the monomer and dimers.

Deriving Novel Quaternary Ammonium Compound Disinfectant Scaffolds from a Natural Product: Mechanistic Insights of the Quaternization of Ianthelliformisamine C.

In the search for novel quaternary ammonium compound (QAC) disinfectants that can evade bacterial resistance, we turned to natural products as a source of inspiration. Herein we used natural product ianthelliformisamine C as a scaffold to design a small library of QACs. We first synthesized ianthelliformisamine C via an amide coupling that allowed for facile purification without the need for protecting groups. We then alkylated and quaternized the internal amines to yield four novel QACs, but all but one demonstrated no antibacterial activity against the tested strains. Using a combination of membrane depolarization and permeabilization assays, we were able to demonstrate that ianthelliformisamine C and the active QAC analog enact cell death via membrane permeabilization, contrary to prior reports on ianthelliformisamine C's mechanism of action.

Quaternary Phosphonium Compound Unveiled as a Potent Disinfectant against Highly Resistant Acinetobacter baumannii Clinical Isolates.

Acinetobacter baumannii is classified as a highest threat pathogen, urgently necessitating novel antimicrobials that evade resistance to combat its spread. Quaternary ammonium compounds (QACs) have afforded a valuable first line of defense against antimicrobial resistant pathogens as broad-spectrum amphiphilic disinfectant molecules. However, a paucity of innovation in this space has driven the emergence of QAC resistance. Through this work, we sought to identify next-generation disinfectant molecules with efficacy against highly resistant A. baumannii clinical isolates. We selected 12 best-in-class molecules from our previous investigations of quaternary ammonium and quaternary phosphonium compounds (QPCs) to test against a panel of 35 resistant A. baumannii clinical isolates. The results highlighted the efficacy of our next-generation compounds over leading commercial QACs, with our best-in-class QAC (2Pyr-11,11) and QPC (P6P-10,10) displaying improved activities with a few exceptions. Furthermore, we elucidated a correlation between colistin resistance and QAC resistance, wherein the only pan-resistant isolate of the panel, also harboring colistin resistance, exhibited resistance to all tested QACs. Notably, P6P-10,10 maintained efficacy against this strain with an IC90 of 3 µM. In addition, P6P-10,10 displayed minimum biofilm eradication concentrations as low as 32 µM against extensively drug resistant clinical isolates. Lastly, examining the development of disinfectant resistance and cross-resistance, we generated QAC-resistant A. baumannii mutants and observed the development of QAC cross-resistance. In contrast, neither disinfectant resistance nor cross-resistance was observed in A. baumannii under P6P-10,10 treatment. Taken together, the results of this work illustrate the need for novel disinfectant compounds to treat resistant pathogens, such as A. baumannii, and underscore the promise of QPCs, such as P6P-10,10, as viable next-generation disinfectant molecules.

Metallocene QACs: The Incorporation of Ferrocene Moieties into monoQAC and bisQAC Structures.

Inspired by the incorporation of metallocene functionalities into a variety of bioactive structures, particularly antimicrobial peptides, we endeavored to broaden the structural variety of quaternary ammonium compounds (QACs) by the incorporation of the ferrocene moiety. Accordingly, 23 ferrocene-containing mono- and bisQACs were prepared in high yields and tested for activity against a variety of bacteria, including Gram-negative strains and a panel of clinically isolated MRSA strains. Ferrocene QACs were shown to be effective antiseptics with some displaying single-digit micromolar activity against all bacteria tested, demonstrating yet another step in the expansion of structural variety of antiseptic QACs.

Broadening Activity of Polymyxin by Quaternary Ammonium Grafting.

Bacterial pathogens continue to impose a tremendous health burden across the globe. Here, we describe a novel series of polymyxin-based agents grafted with membrane-active quaternary ammonium warheads to combine two important classes of Gram-negative antimicrobial scaffolds. The goal was to deliver a targeted quaternary ammonium warhead onto the surface of bacterial pathogens using the outer membrane homing properties of polymyxin. The most potent agents resulted in new scaffolds that retained the ability to target Gram-negative bacteria and had limited toxicity toward mammalian cells. We showed, using a molecular dynamics approach, that the new agents retained their ability to engage in specific interactions with lipopolysaccharide molecules. Significantly, the combination of quaternary ammonium and polymyxin widens the activity to the pathogen Staphylococcus aureus. Our results serve as an example of how two membrane-active agents can be combined to produce a class of novel scaffolds with potent biological activity.

Further Investigations into Rigidity-Activity Relationships in BisQAC Amphiphilic Antiseptics.

Thirty-six biscationic quaternary ammonium compounds were efficiently synthesized in one step to examine the effect of molecular geometry of two-carbon linkers on antimicrobial activity. The synthesized compounds showed strong antimicrobial activity against a panel of both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). While the linker geometry showed only a modest correlation with antimicrobial activity, several of the synthesized bisQACs are promising potential antiseptics due to good antimicrobial activity (MIC≤2 µM) and their higher therapeutic indices compared to previously reported QACs.

Optimized aerial applications of two resmethrin formulations against caged Anopheles quadrimaculatus.

Optimized aerial applications were conducted to assess the efficacy of 2 formulations of resmethrin (Scourge 18-54, Aqua-Scourge 10-30) for control of caged adult Anopheles quadrimaculatus. Micronair AU4000 rotary atomizers were employed to apply the chemical. Both compounds were applied at 0.0035 lb AI/acre (3.92 g AI/ha) with the use of the AGDISP computer model to predict appropriate flight offsets (up to 1,219.2 m). Efficacy was based on bioassays with caged An. quadrimaculatus adults and assessment of impinger-collected droplets. Both compounds provided effective mosquito control. Mean mortality at 24 h posttreatment averaged 80.4% for Scourge, and 80.7% for Aqua-Scourge. Mean droplet sizes, Dv0.5 = 26 microm and 38 microm, and mean density, 74 droplets/cm2 and 41 droplets/cm2, for Scourge and Aqua-Scourge, respectively, were consistent with the bioassay results. Analysis of droplet deposition and mortality failed to reveal a statistical correlation between mortality and deposit volume.

Utility of the Bender Visual-Motor Gestalt Test-Second Edition in the assessment of attention-deficit/hyperactivity disorder.

This study examined the use of the Bender Visual-Motor Gestalt Test-Second Edition (BGT-II) with children diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD). Previous research has examined the relationship of ADHD and visual-motor functioning based on overall developmental scores or specific emotional indicators. Although several studies have examined the relationship of the previous edition of the BGT-II and ADHD symptoms, psychometric issues associated with the original edition limit the validity of the results. The current study examined the utility of the BGT-II in the assessment of behaviors associated with ADHD. A group of 62 subjects diagnosed with ADHD (M=11 yr., 5 mo.; 45 male, 17 female) was compared to a control group of 62 subjects randomly selected from the BGT-II standardization data (M=11 yr., 6 mo; 33 male, 29 female). Several hypotheses were made regarding how areas of deficit, e.g., self-regulation, planning, working memory, and motor control, were expected to manifest in BGT-II performance. With IQ controlled, subjects with ADHD performed more poorly on the BGT-II than subjects with no known disorders; however, the effect size was small (eta(p)=.07). Emotional indicators intended to assess symptoms of ADHD did not demonstrate diagnostic utility.

Confiabilidad intercalificadores y validez de constructo del Test Gestáltico de Bender (segunda versión) / Inter-scorer reliability and construct validity in the Bender Gestalt Test (second version)

Hace algunos años, se ha publicado el nuevo Test Gestáltico de Bender, segunda versión (Bender-II). Esta nueva versión usa el Sistema de Calificación Global (SCG) para obtener los puntajes, que enfatiza la reproducción exacta de los diseños; junto con otros cambios estructurales, consiste en la mayor modificación realizada al Test de Bender para evaluar la habilidad visomotora en varias etapas del desarrollo humano. Pero aún hay pocas investigaciones que han estudiado su funcionamiento psicométrico en muestras hispanas y especialmente el error de medición en el procedimiento de la calificación. Se investigó el efecto de la variabilidad de la calificación del nuevo Bender-II sobre su validez de constructo con una medida de inteligencia. Se administraron el Bender-II y el Test Breve de Inteligencia de Kaufman (K-BIT) a 60 niños preescolares, y tres calificadores calificaron las figuras reproducidas mediante procedimientos estandarizados y el SCG. El análisis comparó las correlaciones obtenidas por cada calificador entre los puntajes del Bender-II y del K-BIT. Se halló que la variabilidad de los puntajes proveniente de la interpretación del SCG afectó moderadamente las correlaciones con el puntaje total y de las subescalas del K-BIT. Un calificador fue menos confiable y sus puntajes mostraron al menos 5% menos variancia compartida al compararlo con los otros calificadores. Se concluye que la interpretación de la validez se puede distorsionar aun cuando el error de medición es moderado pues interaccionan con otras fuentes de error. Esto sugiere que se debe garantizar un buen acuerdo en la calificación de pruebas que requieran juicio.

Although the impact of the measurement error in the accuracy of the classification of subjects and validity correlations is theoretically established, in a practical situation has not been explored the degree of impact on the new Bender-II (Brannigan & Decker, 2003). The practical situation of assessment is that which occurs in the professional context, in which one or more examiners of an assessment team assessing children in a particular institution. The new Bender-II has substantial modifications in its structure and functioning, making it different from the original instrument proposed by Bender (1938, 1946). Structural changes consisted in more of items (16 designs), complementary tests (fine motor and visual perception) and two major tests (Visual Constructive Memory and Visual Motor), the rating method Global Scoring System (GSS) and standardized record sheet for the child's behavior during the test administration. The GSS was created ad hoc for the Bender-II, and it is a method that emphasizes the exact reproduction of the designs; its origin is in the original gestalt approach of Bender. Main studies have been published in the manual (Brannigan & Decker, 2003), and subsequent studies have used the American standardization sample. However, in non-immigrant Hispanic population, to date there are some unpublished and published only one (Merino, 2012); therefore, it is not known how generalizable the findings and psychometric properties obtained in the American standardization sample are. The aim of the study was to examine the effect of the variability of the scoring of designs of the new Bender-II on construct validity with a measure of intelligence. The Bender-II and Kaufman Brief Intelligence Test (K-BIT - Kaufman, A. S. & Kaufman, A. L., 1994) was administered to 60 preschool children (between 4 and 5 years, 33 girls), and three scorers rated the designs reproduced, by standardized procedures and GSS. The analysis consisted of two steps: first, we estimated the consistency and inter-rater agreement using random two-way intraclass correlations (McGraw & Wong, 1996; Shrout & Fleiss, 1979). Second, for each scorer, correlations were calculated between scores on the Bender-II and K-BIT, and finally these correlations were compared with a test for dependent correlations with a common element (Steiger, 1980, Williams, 1959). The results indicate that there were slight differences between two scorers, but one of them had comparatively lower coefficients of consistency and agreement. In the all scorers, the magnitude of the consistency coefficients (> .85) and agreement (> .84) between the qualifiers indicate good levels of concordance with even moderate exercise time (two or three sessions). Correlations between scores on the Bender-II and K-BIT were around .43 and .61, and the lowest correlations occurred in the scorer that showed less consistency and agreement with other scorers, clearly indicating the impact of measurement error in the validity correlations. Compared with one of the rating, this difference was statistically significant, and the percentage reduction of covariance was at least 5%. Finally, the results indicate several points. First, we present other evidence for inter-rater reliability of the Bender-II, and that there were good levels of agreement and consistency. Second, there is potentially a reduction in the correlations of validity when a scorer has trouble for interpret consistently and correctly Global Scoring System. Correlations decreased, however, are not equal in all the scorers, and therefore must be verified the goodness of fit between scorer and the Bender it's qualification method approach. The results can be are idiosyncratic to the sample and study conditions, and the sample size constraints threaten the generalizability of the findings. However, the study conditions are close to professional practice and therefore can be generalized to some extent. In addition, can serve as a baseline to compare future studies of reliability in the Bender-II.

Validity of two selected-item short forms of the WAIS-III in an intellectually deficient sample.

Various short forms of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III; D. Wechsler, 1997) have been investigated, but limited information is available regarding the usefulness of any WAIS-III abbreviation with intellectually deficient individuals. Our study compared the validities of two WAIS-III selected-item short forms in a sample of 59 individuals with full scale IQs (FSIQs) of 79 or lower. The performance of both short forms was adequate, but the results gave a consistent edge to an adapted version of the Satz-Mogel (1962) short form in comparison to the abbreviated form by J. H. Wymer, K. Rayls, and M. T. Wagner (2003). The correlation (r = .98) of Satz-Mogel estimates with WAIS-III FSIQ scores was slightly higher than the correlation (r = .97) for estimates from Wymer et al.'s abbreviated form, and Satz-Mogel estimates did not differ significantly from actual FSIQs. In comparison to individual classification (FSIQ > 70 versus FSIQ < or = 70) obtained with the full WAIS-III, the misclassification rate was somewhat lower for the Satz-Mogel short form. Although both short forms performed reasonably well, practitioners should be cautious when utilizing any short form to make decisions about individuals.