Direct modifications of the cyclic peptide Polymyxin B leading to analogues with enhanced in vitro antibacterial activity.

Synthetic modifications have been made directly to the cyclic peptide core of polymyxin B, enabling the further understanding of structure activity relationships of this antimicrobial peptide. Such modified polymyxins are also substrates for enzymic hydrolysis, enabling the synthesis of a variety of semi-synthetic analogues, resulting in compounds with increased in vitro antibacterial activity.

Bridging Multidimensional Models of Ethnic-Racial and Gender Identity Among Ethnically Diverse Emerging Adults.

The purpose of this study was to integrate and validate a multidimensional model of ethnic-racial identity and gender identity borrowing constructs and measures based on social identity and gender identity theories. Participants included 662 emerging adults (M age  = 19.86 years; 75 % female) who self-identified either as Asian American, Latino/a, or White European American. We assessed the following facets separately for ethnic-racial identity and gender identity: centrality, in-group affect, in-group ties, self-perceived typicality, and felt conformity pressure. Within each identity domain (gender or ethnicity/race), the five dimensions generally indicated small-to-moderate correlations with one another. Also, correlations between domains for each dimension (e.g., gender typicality and ethnic-racial typicality) were mostly moderate in magnitude. We also noted some group variations based on participants' ethnicity/race and gender in how strongly particular dimensions were associated with self-esteem. Finally, participants who scored positively on identity dimensions for both gender and ethnic-racial domains indicated higher self-esteem than those who scored high in only one domain or low in both domains. We recommend the application of multidimensional models to study social identities in multiple domains as they may relate to various outcomes during development.

Influence of Lipophilicity on the Antibacterial Activity of Polymyxin Derivatives and on Their Ability to Act as Potentiators of Rifampicin.

Novel polymyxin derivatives are often classified either as having direct activity against Gram-negative pathogens or as compounds inactive in their own right, which through permeabilization of the outer membrane act as potentiators of other antibiotics. Here, we report the systematic investigation of the influence of lipophilicity on microbiological activity (including against strains with reduced susceptibility to polymyxins), potentiation of rifampicin, and in vitro toxicity within a series of next-generation polymyxin nonapeptides. We demonstrate that the lipophilicity at the N-terminus and amino acids 6 and 7 in the cyclic peptide core is interchangeable and that the activity, ability to potentiate, and cytotoxicity all appear to be primarily driven by overall lipophilicity. Our work also suggests that the characterization of a polymyxin molecule as either a direct acting compound or a potentiator is more of a continuum that is strongly influenced by lipophilicity rather than as a result of fundamentally different modes-of-action.

Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206.

Polymyxins are an important class of antibiotics for the treatment of bacterial infections due to multidrug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here, we report a series of promising next generation polymyxin nonapeptides identified on the basis of our understanding of the relationship of structure with activity, cytotoxicity, and kidney compartment accumulation. We demonstrate that nonapeptides with an amine-containing N-terminal moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared to polymyxin B. We further demonstrate that compounds with a ß-branched aminobutyrate N-terminus with an aryl substituent offer a promising combination of low cytotoxicity and kidney exposure, leading to low toxicity in the mouse. From this series, SPR206 has been selected as a development candidate.