There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated γ-AApeptides as antimicrobial agents. These lipo-γ-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure-function relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-γ-AApeptide did not induce drug resistance in S. aureus, even after 17 rounds of passaging. These results suggest that the lipo-γ-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics.

We report the identification of a new class of antimicrobial peptidomimetics-γ-AApeptides with potent and broad-spectrum activity, including clinically-relevant strains that are unresponsive to most antibiotics. They are also not prone to select for drug-resistance.

Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against Alzheimer’s disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate cohorts consisting of 124 total individuals (65–88 years old) were cognitively assessed and a blood sample taken for caffeine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2–4 year period to determine the extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine levels at study onset were substantially lower (−51%) in mild cognitive impairment (MCI) subjects who later progressed to dementia (MCI→DEM) compared to levels in stable MCI subjects (MCI→MCI). Moreover, none of the MCI→DEM subjects had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCI→MCI subjects had blood caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (≈6 µM) in MCI subjects were associated with no conversion to dementia during the ensuing 2–4 year follow-up period. Among the 11 cytokines measured in plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCI→DEM subjects, but not in stable MCI→MCI subjects with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset, particularly for those who already have MCI.

Antimicrobial drug resistance is one of the greatest threats facing mankind. Antimicrobial peptides (AMPs) can potentially circumvent drug resistance, probably through a bacterial membrane-disruption mechanism. However, they suffer from low in vivo stability, potential immunogenicity, and difficulty in optimization. The development of antimicrobial peptidomimetics is therefore an emerging research area as they avoid the potential disadvantages of AMPs. Cyclic peptidomimetics are of significant interest since constraints induced by cyclization are expected to further improve their antimicrobial activity. Nonetheless, the report of cyclic oligomeric peptidomimetics for antimicrobial development is rare. Herein, for the first time, we report the design and synthesis of cyclic g-AApeptides via an on-resin cyclization. These cyclic g-AApeptides are potent and broad-spectrum active against fungus and multidrug resistant Gram-positive and Gram-negative bacterial pathogens. Our results demonstrate the potential of cyclic g-AApeptides as a new class of antibiotics to circumvent drug resistance by mimicking the bactericidal mechanism of AMPs. Meanwhile, the facile synthesis of cyclic g-AApeptides may further expand the applications of g-AApeptides in biomedical sciences.

We report a new class of peptide mimetics, α-AApeptides, that display broad-spectrum activity against both Gram-negative and Gram-positive bacteria and fungi. With non-hemolytic activity, resistance to protease hydrolysis, and easy sequence programmability, α-AApeptides may emerge as a novel class of antibiotics.

Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer's disease (AD). Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-β levels/deposition through suppression of both β- and γ-secretase. Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone. In both AβPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6. Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines. The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines. Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine's established ability to suppress Aβ production. We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD.

Partial nitritation providing a suitable effluent for subsequent anammox is a critical step in a two-stage autotrophic nitrogen removal system. This study demonstrates an innovative approach for attaining partial nitritation in an acidic bioreactor operating at a slightly low pH (i.e., 5–6). This approach is based on our hypothesis in this study that acid-tolerant ammonia-oxidizing bacteria (AOB) can produce nitrite and protons to self-sustain free nitrous acid (FNA, NO2 – + H+ ↔ HNO2) at a parts per million level, as an inhibitor of nitrite-oxidizing bacteria (NOB). With influent nitrogen of about 200 mg/L and operating conditions of high dissolved oxygen, long sludge retention time, and moderate temperature, a lab-scale acidic bioreactor with FNA up to 2 mg of HNO2-N/L successfully established stable nitrite accumulation in the effluent for 200 days, with an average ratio [NO2 –/(NO2 – + NO3 –)] exceeding 95%. A 16S rRNA amplicon sequencing analysis showed that Nitrosospira was the dominant AOB in the biomass of the bioreactor, while Nitrosomonas and Nitrospira, two typical nitrifying genera in neutral wastewater treatment, both disappeared after the startup of partial nitritation. Kinetic characterization revealed that Nitrosospira had a substrate affinity of 11.4–16.5 mg of total ammonia (NH4 + + NH3)/L. It also revealed that less than 3.5 mg of HNO2-N/L FNA did not inhibit AOB activity significantly. Acidic operation is economically attractive because it can be achieved via acidophilic ammonia oxidation without adding chemical acid. However, hazardous gas, nitric oxide (NO), should be removed from gas produced by acidic nitrifying bioreactors.

Host-defense peptides (HDPs) such as magainin 2 have emerged as potential therapeutic agents combating antibiotic resistance. Inspired by their structures and mechanism of action, herein we report the first example of antimicrobial helical sulfono-γ-AApeptide foldamers. The lead molecule displays broad-spectrum and potent antimicrobial activity against multi-drug-resistant Gram-positive and Gram-negative bacterial pathogens. Time-kill studies and fluorescence microscopy suggest that sulfono-γ-AApeptides eradicate bacteria by taking a mode of action analogous to that of HDPs. Clear structure-function relationships exist in the studied sequences. Longer sequences, presumably adopting more-defined helical structures, are more potent than shorter ones. Interestingly, the sequence with less helical propensity in solution could be more selective than the stronger helix-forming sequences. Moreover, this class of antimicrobial agents are resistant to proteolytic degradation. These results may lead to the development of a new class of antimicrobial foldamers combating emerging antibiotic-resistant pathogens.