The prevalence of drug-resistant bacteria drives the quest for new antimicrobials, including those that are not expected to readily engender resistance. One option is to mimic Nature's most ubiquitous means of controlling bacterial growth, antimicrobial peptides, which have evolved over eons. In general, bacteria remain susceptible to these peptides. Human antimicrobial peptides play a central role in innate immunity, and deficiencies in these peptides have been tied to increased rates of infection. However, clinical use of antimicrobial peptides is hampered by issues of cost and stability. The development of nonpeptide mimics of antimicrobial peptides may provide the best of both worlds: a means of using the same mechanism chosen by Nature to control bacterial growth without the problems associated with peptide therapeutics. The ceragenins were developed to mimic the cationic, facially amphiphilic structures of most antimicrobial peptides. These compounds reproduce the required morphology using a bile-acid scaffolding and appended amine groups. The resulting compounds are actively bactericidal against both gram-positive and gram-negative organisms, including drug-resistant bacteria. This antimicrobial activity originates from selective association of the ceragenins with negatively charged bacterial membrane components. Association has been studied with synthetic models of bacterial membrane components, with bacterial lipopolysaccharide, with vesicles derived from bacterial phospholipids, and with whole cells. Comparisons of the antimicrobial activities of ceragenins and representative antimicrobial peptides suggest that these classes of compounds share a mechanism of action. Rapid membrane depolarization is caused by both classes as well as blebbing of bacterial membranes. Bacteria express the same genes in response to both classes of compounds. On the basis of the antibacterial activities of ceragenins and preliminary in vivo studies, we expect these compounds to find use in augmenting or replacing antimicrobial peptides in treating human disease.

Expression of the Pho regulon in Escherichia coli is induced in response to low levels of environmental phosphate (P i ). Under these conditions, the high-affinity PstSCAB 2 protein (i.e., with two PstB proteins) is the primary P i transporter. Expression from the pstSCAB-phoU operon is regulated by the PhoB/PhoR twocomponent regulatory system. PhoU is a negative regulator of the Pho regulon; however, the mechanism by which PhoU accomplishes this is currently unknown. Genetic studies of phoU have proven to be difficult because deletion of the phoU gene leads to a severe growth defect and creates strong selection for compensatory mutations resulting in confounding data. To overcome the instability of phoU deletions, we employed a promoter-swapping technique that places expression of the phoBR two-component system under control of the P tac promoter and the lacO ID regulatory module. This technique may be generally applicable for controlling expression of other chromosomal genes in E. coli. Here we utilized P phoB ::P tac and P pstS ::P tac strains to characterize phenotypes resulting from various ⌬phoU mutations. Our results indicate that PhoU controls the activity of the PstSCAB 2 transporter, as well as its abundance within the cell. In addition, we used the P phoB ::P tac ⌬phoU strain as a platform to begin characterizing new phoU mutations in plasmids.

Ceragenin CSA-138 appears well suited for providing an innate immune-like function to abiotic hydrogel contact lenses for extended periods of time. Elution of even low concentrations of CSA-138 (<0.5 μg) is sufficient to eliminate inocula of 10⁶ CFU of S. aureus and P. aeruginosa.

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Background and objectivesThe objective of the study was to determine if injection of local anesthetic into the vastus medialis and sartorius muscles adjacent to the adductor canal produces sensory changes comparable with adductor canal block (ACB). This could result in a technically easier and potentially safer alternative to ACB.MethodsIn this randomized controlled trial, patients received either ACB (n=20) or a simplified adductor canal (SAC) block performed using a new fenestrated nerve block needle (n=20). The time to perform each block as well as the number of attempts to position the needle were evaluated. A non-inferiority test was used to compare pain scores and opioid requirements for the ACB and the SAC block.ResultsThe SAC block was performed more rapidly, with fewer needle passes, and had a higher success rate than the ACB. Three block failures and two vessel punctures were observed in the ACB group, while none of these events occurred in SAC block patients. Analgesia and opioid consumption for patients treated with the SAC block were not inferior to ACB.ConclusionThe SAC block is technically easier to perform and potentially safer than ACB. This procedure can be performed using easily visible ultrasound landmarks and has the potential for use among a wide range of healthcare providers.Trial registration number NCT02786888.