Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance.

Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant S. aureus; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in S. aureus. This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.

Preclinical Evaluation of a Fluorescent Probe Targeting Receptor CDCP1 for Identification of Ovarian Cancer.

Optimal cytoreduction for ovarian cancer is often challenging because of aggressive tumor biology and advanced stage. It is a critical issue since the extent of residual disease after surgery is the key predictor of ovarian cancer patient survival. For a limited number of cancers, fluorescence-guided surgery has emerged as an effective aid for tumor delineation and effective cytoreduction. The intravenously administered fluorescent agent, most commonly indocyanine green (ICG), accumulates preferentially in tumors, which are visualized under a fluorescent light source to aid surgery. Insufficient tumor specificity has limited the broad application of these agents in surgical oncology including for ovarian cancer. In this study, we developed a novel tumor-selective fluorescent agent by chemically linking ICG to mouse monoclonal antibody 10D7 that specifically recognizes an ovarian cancer-enriched cell surface receptor, CUB-domain-containing protein 1 (CDCP1). 10D7ICG has high affinity for purified recombinant CDCP1 and CDCP1 that is located on the surface of ovarian cancer cells in vitro and in vivo. Our results show that intravenously administered 10D7ICG accumulates preferentially in ovarian cancer, permitting visualization of xenograft tumors in mice. The data suggest CDCP1 as a rational target for tumor-specific fluorescence-guided surgery for ovarian cancer.

Adult stem cells in tissue engineering.

Tissue engineering is a rapidly evolving field of research that has yet to fulfil its promise in the translation and potential application of adult stem cells in clinical practice. Recently, it has become apparent that specific adult stem cells are capable of transdifferentiation. The successful application of adult stem cells is thought to be central in creating truly biomimetic tissue. Although still most widely utilized, research suggests that in the future, bone marrow-derived stem cells may no longer be considered the most suitable candidates for use in tissue engineering. Independent studies have successfully engineered a range of tissues in vitro and in vivo using hair follicle- and adipose-derived stem cells. Owing to their potency, relative abundance and noninvasive extraction, these populations may be the most promising studied to date. This review aims to discuss these candidate adult stem cell populations in an attempt to assess the most promising avenues of research.