Optimization of the Antibacterial Spectrum and the Developability Profile of the Novel-Class Natural Product Corramycin.

Corramycin 1 is a novel zwitterionic antibacterial peptide isolated from a culture of the myxobacterium Corallococcus coralloides. Though Corramycin displayed a narrow spectrum and modest MICs against sensitive bacteria, its ADMET and physchem profile as well as its high tolerability in mice along with an outstanding in vivo efficacy in an Escherichia coli septicemia mouse model were promising and prompted us to embark on an optimization program aiming at enlarging the spectrum and at increasing the antibacterial activities by modulating membrane permeability. Scanning the peptidic moiety by the Ala-scan strategy followed by key stabilization and introduction of groups such as a primary amine or siderophore allowed us to enlarge the spectrum and increase the overall developability profile. The optimized Corramycin 28 showed an improved mouse IV PK and a broader spectrum with high potency against key Gram-negative bacteria that translated into excellent efficacy in several in vivo mouse infection models.

Epithelial phenotypic changes detect cyclosporine in vivo nephrotoxicity at a reversible stage.

BACKGROUND: A widely used immunosuppressant, cyclosporine A (CsA), conveys long-term nephrotoxicity in some patients. However, no specific marker is presently available. In both native and transplanted human kidneys, epithelial phenotypic changes (EPCs) suggestive of epithelial to mesenchymal transition (EMT) are expressed in various diseases and are prognostic with respect to progression of interstitial fibrosis. We hypothesized that CsA is able to trigger these EPCs in tubular cells in vivo. METHODS: We studied the kinetics of the EMT markers ß-catenin, snail, vimentin, collagen III, and HSP47 at the messenger RNA and protein levels in the kidneys from rats injected with 15 mg/kg/day of CsA or its vehicle. We investigated several therapeutic strategies available to block EMT in this model. RESULTS: By 2 weeks, CsA had induced histological changes (tubular dilatation and vacuoles) and overexpression of EMT-related genes. This up-regulation of the EMT program was associated with tubular, not interstitial, overexpression of mesenchymal markers. Angiotensin II and endothelin receptor antagonists failed to prevent this CsA-induced EMT. Interestingly, CsA withdrawal led to the gradual regression of histological lesions and EMT, demonstrating that it not only prevents progression but also allows healing of renal injury. CONCLUSION: Our study suggests that detecting EPC could help to identify ongoing renal CsA-induced toxicity at an early and reversible stage.

[Interstitial fibrosis in renal grafts: On the way to a better detection]. / Fibrose interstitielle du greffon rénal : vers un meilleur dépistage.

In renal grafts, the progression of interstitial fibrosis and tubular atrophy (IF/TA) is exponential during the first months post-transplant. Consequently, roughly 40% of the cadaveric grafts will function less than ten years. There is, however, no specific strategy to halt fibrogenesis, i.e. the progression of fibrosis with time, in kidney recipients. Epithelial to mesenchymal transition (EMT) is a biological process used to disperse cells during embryogenesis. In the setting of injury, it is also a mechanism to escape cellular death. The last five years, several studies demonstrated that EMT does occur in tubular epithelial cells, which have been shown to loose the expression of epithelial markers, and acquire the expression of mesenchymal proteins, like vimentin. The aim of this review is triple: 1) discuss the connections between EMT and the context of transplantation; 2) explain how EMT markers may be useful in clinical practice, as promising surrogate markers for fibrogenesis; 3) discuss some therapeutic perspectives.