Promiscuous, persistent and problematic: insights into current enterococcal genomics to guide therapeutic strategy.

Vancomycin-resistant enterococci (VRE) are major opportunistic pathogens and the causative agents of serious diseases, such as urinary tract infections and endocarditis. VRE strains mainly include species of Enterococcus faecium and E. faecalis which can colonise the gastrointestinal tract (GIT) of patients and, following growth and persistence in the gut, can transfer to blood resulting in systemic dissemination in the body. Advancements in genomics have revealed that hospital-associated VRE strains are characterised by increased numbers of mobile genetic elements, higher numbers of antibiotic resistance genes and often lack active CRISPR-Cas systems. Additionally, comparative genomics have increased our understanding of dissemination routes among patients and healthcare workers. Since the efficiency of currently available antibiotics is rapidly declining, new measures to control infection and dissemination of these persistent pathogens are urgently needed. These approaches include combinatory administration of antibiotics, strengthening colonisation resistance of the gut microbiota to reduce VRE proliferation through commensals or probiotic bacteria, or switching to non-antibiotic bacterial killers, such as bacteriophages or bacteriocins. In this review, we discuss the current knowledge of the genomics of VRE isolates and state-of-the-art therapeutic advances against VRE infections.

Inhibition of the endosomal recycling pathway downregulates HER2 activation and overcomes resistance to tyrosine kinase inhibitors in HER2-positive breast cancer.

The development of HER2-targeted therapies has led to a dramatic improvement in outcomes for breast cancer patients. However, nearly all patients with metastatic HER2-positive breast cancer will eventually progress on these therapies due to innate or acquired resistance. Recent evidence suggests that the endosomal recycling of HER2 plays an important role in regulating its oncogenic signalling. Here we report that the expression of Rab coupling protein (RCP), a key regulator of endosomal recycling, positively correlates with that of HER2 and HER3 in breast tumours, and high RCP expression is predictive of poor relapse-free and overall survival in patients with HER2-amplified breast cancer. Chemical and genetic inhibition of endosomal recycling leads to a reduction in the total cellular levels of HER2 and HER3 and inhibits the activation of their downstream signalling pathways. We find that HER2 and HER3 that have been internalised from the plasma membrane are diverted to lysosomes for degradation when endosomal recycling is blocked. Primaquine (PQ), a small molecule inhibitor of the endosomal recycling pathway, synergises with HER2-targeting tyrosine kinase inhibitors and overcomes innate and acquired resistance to these TKIs. Moreover, TKI-induced drug tolerant persister cells are vulnerable to endosomal recycling inhibitors. These findings suggest that inhibition of endosomal recycling represents a promising therapeutic strategy for treating drug resistant HER2-positive breast cancer.