Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs—from a library of 183 derivatives—that are potent inhibitors of DNA gyrase and are active against clinical strains of gram-negative bacteria (Escherichia coli, Shigella flexneri, and Salmonella enterica; 3 of 10 wild-type strains tested) and gram-positive bacteria (Bacillus spp., Enterococcus spp., Staphylococcus spp., and Streptococcus spp.; all 9 of the wild-type strains tested). E. coli strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC50s of 47–170 nM) but do not alter the enzyme’s ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (gyrA and gyrB genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.

Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad-spectrum antibacterial agents with exciting activity as antibiotic adjuvants. We synthesized 5-alkyloxytryptamine analogs and found that an alkyl chain length of 6–12 carbons and a primary ammonium group are necessary for the antibacterial activity of the compounds, and an alkyl chain length of 6–10 carbons increased the membrane permeability of gram-positive and gram-negative bacteria. Although several of the most potent analogs also have activity against the membranes of human embryonic kidney cells, we demonstrate that below the minimum inhibitory concentration (MIC)—where mammalian cell toxicity is low—these compounds may be successfully used as adjuvants for chloramphenicol, tetracycline, ciprofloxacin, and rifampicin against clinical strains of Salmonella typhimurium, Acinetobacter baumannii and Staphylococcus aureus, reducing MIC values by as much as several logs.

Housing instability is variably defined but generally encompasses difficulty paying rent, living in poor or overcrowded conditions, moving frequently, or spending the majority of household income on housing costs. While there is strong evidence that people experiencing homelessness (i.e., lack of regular housing) are at increased risk for cardiovascular disease, obesity, and diabetes, less is known about housing instability and health. We synthesized evidence from 42 original research studies conducted in the United States examining the association of housing instability and cardiometabolic health conditions of overweight/obesity, hypertension, diabetes, and cardiovascular disease. The included studies varied widely in their definitions and methods of measuring housing instability, but all exposure variables were related to housing cost burden, frequency of moves, living in poor or overcrowded conditions, or experiencing eviction or foreclosure, measured at either the individual household level or at a population level. We also included studies examining the impact of receipt of government rental assistance, which serves as a marker of housing instability given that its purpose is to provide affordable housing for low-income households. Overall, we found mixed but generally adverse associations between housing instability and cardiometabolic health, including higher prevalence of overweight/obesity, hypertension, diabetes, and cardiovascular disease; worse hypertension and diabetes control; and higher acute health care utilization among those with diabetes and cardiovascular disease. We propose a conceptual framework for pathways linking housing instability and cardiometabolic disease that could be targeted in future research and housing policies or programs.