Adaptive Evolution of Escherichia coli to an α-Peptide/β-Peptoid Peptidomimetic Induces Stable Resistance.

Antimicrobial peptides (AMPs) and synthetic analogues thereof target conserved structures of bacterial cell envelopes and hence, development of resistance has been considered an unlikely event. However, recently bacterial resistance to AMPs has been observed, and the aim of the present study was to determine whether bacterial resistance may also evolve against synthetic AMP analogues, e.g. α-peptide/β-peptoid peptidomimetics. E. coli ATCC 25922 was exposed to increasing concentrations of a peptidomimetic (10 lineages), polymyxin B (10 lineages), or MilliQ water (4 lineages) in a re-inoculation culturing setup covering approx. 500 generations. All 10 lineages exposed to the peptidomimetic adapted to 32 × MIC while this occurred for 8 out of 10 of the polymyxin B-exposed lineages. All lineages exposed to 32 × MIC of either the peptidomimetic or polymyxin B had a significantly increased MIC (16-32 ×) to the selection agent. Five transfers (≈ 35 generations) in unsupplemented media did not abolish resistance indicating that resistance was heritable. Single isolates from peptidomimetic-exposed lineage populations displayed MICs against the peptidomimetic from wild-type MIC to 32 × MIC revealing heterogeneous populations. Resistant isolates showed no cross-resistance against a panel of membrane-active AMPs. These isolates were highly susceptible to blood plasma antibacterial activity and were killed when plasma concentrations exceeded ≈ 30%. Notably, MIC of the peptidomimetic against resistant isolates returned to wild-type level upon addition of 25% plasma. Whole-genome sequencing of twenty isolates from four resistant lineages revealed mutations, in murein transglycosylase D (mltD) and outer-membrane proteins, which were conserved within and between lineages. However, no common resistance-conferring mutation was identified. We hypothesise that alterations in cell envelope structure result in peptidomimetic resistance, and that this may occur via several distinct mechanisms. Interestingly, this type of resistance result in a concomitant high susceptibility towards plasma, and therefore the present study does not infer additional concern for peptidomimetics as future therapeutics

Discrimination and Hate Crimes in the Context of Neighborhood Poverty and Stressors Among HIV-Positive African-American Men Who Have Sex with Men

In a sample of HIV-positive African-American men who have sex with men (MSM), we examined neighborhood factors that may contextualize perceived discrimination from three intersecting stigmatized characteristics: race, HIV status, and sexual orientation. HIV-positive African-American MSM (N = 162, mean age = 44, SD = 8) provided information on neighborhood-related stressors and discrimination experiences related to being Black, HIV-positive, or perceived as gay. Residential ZIP codes and US Census data were used to determine neighborhood poverty rates. Regressions, controlling for socio-demographics, indicated that (1) higher neighborhood poverty was significantly related to more frequent experiences with hate crimes (Gay-related: b = 1.15, SE = .43, p < .008); and (2) higher neighborhood-related stressors were significantly related to more frequent discrimination (Black-related: b = .91, SE = .28, p = .001; gay-related: b = .71, SE = .29, p = .01; and HIV-related: b = .65, SE = .28, p = .02) and hate crimes (Gay-related: b = .48, SE = .13, p = .001; and Black-related: b = .28, SE = .14, p = .04). For HIV-positive African-American MSM, higher neighborhood poverty and related stressors are associated with experiencing more discrimination and hate crimes. Interventions for this group should promote individual- and neighborhood-level socioeconomic empowerment and stigma reduction