The emergence of infections by carbapenem resistant Enterobacteriaceae (CRE) pathogens has created an urgent public health threat, as carbapenems are among the drugs of last resort for infections caused by a growing fraction of multi-drug resistant (MDR) bacteria. There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. Here, we report on the efficacy of a novel macrocyclic peptide, minimized theta-defensin (MTD)-12813 in CRE sepsis. MTD12813 is a theta-defensin inspired cyclic peptide that is highly effective against CRE pathogens K. pneumoniae and E. coli in vivo. In mouse septicemia models, single dose administration of MTD12813 significantly enhanced survival by promoting rapid host-mediated bacterial clearance and by modulating pathologic cytokine responses, restoring immune homeostasis, and preventing lethal septic shock. The peptide lacks direct antibacterial activity in the presence of mouse serum or in peritoneal fluid, further evidence for its indirect antibacterial mode of action. MTD12813 is highly stable in biological matrices, resistant to bacterial proteases, and nontoxic to mice at dose levels 100 times the therapeutic dose level, properties which support further development of the peptide as a first in class anti-infective therapeutic.
Preservation of existing trees is one of the few tools available to communities seeking to maintain or increase tree canopy coverage. This study compared the knowledge and activities of builders in an urban locale with a strict tree preservation ordinance and rigorous enforcement against a rural locale with no tree preservation ordinance. Overall, there were more similarities than differences between the two groups though some of those differences are very important. Urban builders and rural builders scored a very similar average of correct responses on questions testing their knowledge: 63% and 65%, respectively. The major difference between urban and rural appears to be in activities as dictated by ordinance. Urban builders were more likely to consult tree preservation experts and use tree fence to create tree protection zones. The successful tree preservation outcomes in the urban community are likely a direct result of ordinance requirements and enforcement by the City Forester, not builders’ knowledge or their conscious decisions.
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