Structure-activity relationships and mechanism of action of tetragomycin derivatives as inhibitors of Staphylococcus aureus staphyloxanthin biosynthesis.

Despite the main strategy to overcome bacterial resistance has focused on the development of more potent antimicrobial agents, the evolutionary pressure caused by such drugs makes this strategy limited. Molecules that interfere with virulence factors appear as a promising alternative though, as they cause reduced selective pressure. As a matter of fact, staphyloxanthin biosynthesis inhibition (STXBI) has been pursued as promising strategy to reduce S. aureus virulence. Herein, we report the inhibitory profile of 27 tetrangomycin derivatives over staphyloxanthin production. The experimental result showed that naphthoquinone dehydro-α-lapachone (25 - EC50 = 57.29 ± 1.15 µM) and 2-Isopropylnaphtho[2,3-b]furan-4,9-dione (26 EC50 = 82.10 ± 1.09 µM) are the most potent compounds and suggest that hydrogen acceptor groups and lipophilic moieties decorating the naphthoquinone ring are crucial for STXBI. In addition, we present an in situ analysis, through RAMAN spectroscopy, that is inexpensive and might be employed to probe the mechanism of action of staphyloxanthin biosynthesis inhibitors. Therefore, our molecular simplification strategies afforded promising lead compounds for the development of drugs that modulate S. aureus staphyloxanthin biosynthesis.

Overweight and Abdominal Obesity Association with All-Cause and Cardiovascular Mortality in the Elderly Aged 80 and Over: A Cohort Study.

OBJECTIVE: To evaluate the association between overweight and abdominal obesity with all-cause and cardiovascular mortality in the elderly aged 80 and over. DESIGN: A prospective cohort study. SETTING: A population-based study of community-dwelling very elderly adults in a city in southern Brazil. PARTICIPANTS: 236 very elderly adults, number that represents 85% of the population aged 80 and over living in the city in the period (mean age 83.4 ± 3.2). MEASUREMENTS: Overweight and abdominal obesity were assessed using recommended cut-off points for body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and waist-height ratio (WHtR). The association between these anthropometric measurements and all-cause and cardiovascular mortality were independently estimated by Cox proportional hazards model. Kaplan-Meier was used to assess survival time. RESULTS: Increased WC (>80cm F and >94cm M) and WHtR (>0.53 F and >0.52 M) were associated with lower all-cause mortality, but only WHtR remained associated even after controlling for residual confounding (HR 0.55 CI95% 0.36-0.84; p<0.001). Additionally increased WC was independently associated with lower mortality from cardiovascular diseases (HR 0.57 CI95% 0.34-0.95; p<0.030). BMI and WHR did not show significant independent association with mortality in the main analysis. CONCLUSION: Greater abdominal fat accumulation, as estimated by WC and WHtR, presented an association with lower allcause and cardiovascular mortality in the elderly aged 80 and over, but not by BMI and WHR.