Ribosome Rescue Inhibitors Kill Actively Growing and Nonreplicating Persister Mycobacterium tuberculosis Cells.

The emergence of Mycobacterium tuberculosis (MTB) strains that are resistant to most or all available antibiotics has created a severe problem for treating tuberculosis and has spurred a quest for new antibiotic targets. Here, we demonstrate that trans-translation is essential for growth of MTB and is a viable target for development of antituberculosis drugs. We also show that an inhibitor of trans-translation, KKL-35, is bactericidal against MTB under both aerobic and anoxic conditions. Biochemical experiments show that this compound targets helix 89 of the 23S rRNA. In silico molecular docking predicts a binding pocket for KKL-35 adjacent to the peptidyl-transfer center in a region not targeted by conventional antibiotics. Computational solvent mapping suggests that this pocket is a druggable hot spot for small molecule binding. Collectively, our findings reveal a new target for antituberculosis drug development and provide critical insight on the mechanism of antibacterial action for KKL-35 and related 1,3,4-oxadiazole benzamides.

Persistent organic pollutants in outmigrant juvenile chinook salmon from the Lower Columbia Estuary, USA.

Although chemical contaminants are recognized as a potential factor contributing to the salmon declines in the Pacific Northwest, United States, information on contaminant concentrations in threatened and endangered salmon from the Columbia Estuary is limited. In this study we monitored exposure to several persistent organic pollutants [polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethanes (DDTs) and other organochlorine pesticides] in outmigrant juvenile fall chinook salmon (Oncorhynchus tschawytscha) in the Lower Columbia River, and evaluated the potential for adverse effects on salmon and the estuarine food web. Contaminants were measured in whole bodies and stomach contents of subyearling to yearling chinook collected in 2001 and 2002 from sites near the confluence of the Columbia and Willamette Rivers, Longview, and within the lower Estuary. The contaminants detected at highest concentrations in salmon whole bodies were PCBs and DDTs. Average concentrations of PCBs in salmon from the sampling sites ranged from 1300 to 14,000 ng/g lipid, in some cases exceeding the recently estimated threshold for adverse health effects in juvenile salmonids of 2400 ng/g lipid. Average DDT concentrations ranged from 1800 to 27,000 ng/g lipid. These levels are among the highest measured in juvenile salmon from Pacific Northwest estuaries to date. Concentrations of PCBs and DDTs in salmon whole bodies showed no clear spatial gradient from the Willamette/Columbia Confluence to the mouth of the Columbia, but tended to be higher in larger fish and older fish, suggesting a correlation with estuarine residence time. PCBs, DDTs, and PAHs were all found in salmon stomach contents, indicating that prey is a source of exposure. Hatchery feed may have contributed to contaminant body burdens in those fish that were of hatchery origin. Contaminant body burdens in salmon were poorly correlated with contaminant concentrations previously measured in local bed sediments, suggesting that pelagic as well as benthic sources are important in determining salmon exposure.