A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.
Diverse pathogenic agents often utilize overlapping host networks, and hub proteins within these networks represent attractive targets for broad-spectrum drugs. Using bacterial toxins, we describe a new approach for discovering broad-spectrum therapies capable of inhibiting host proteins that mediate multiple pathogenic pathways. This approach can be widely used, as it combines genetic-based target identification with cell survival-based and protein function-based multiplex drug screens, and concurrently discovers therapeutic compounds and their protein targets. Using B-lymphoblastoid cells derived from the HapMap Project cohort of persons of African, European, and Asian ancestry we identified host caspases as hub proteins that mediate the lethality of multiple pathogenic agents. We discovered that an approved drug, Bithionol, inhibits host caspases and also reduces the detrimental effects of anthrax lethal toxin, diphtheria toxin, cholera toxin, Pseudomonas aeruginosa exotoxin A, Botulinum neurotoxin, ricin, and Zika virus. Our study reveals the practicality of identifying host proteins that mediate multiple disease pathways and discovering broad-spectrum therapies that target these hub proteins.
The incidence of hip fractures continues to rise. This study is the first evaluation of a new intramedullary implant, the Veronail, that provides double axis fixation into the femoral head and allows the surgeon to choose whether to use sliding or fixed locked proximal screw fixation for trochanteric femoral fractures. The fractures were classified according to the AO classification, and function was assessed with the Modified Harris Hip Score. 111 patients with trochanteric fractures were evaluated in eight Italian hospitals. The stable 31.A1 fractures were treated with sliding proximal screws, the subtrochanteric 31.A3 fractures with converging proximal screws, and the unstable 31.A2 fractures were treated with both types of proximal fixation. The unstable fractures treated with locked converging screws had the same function at one year as those treated with sliding screws. This study suggests a possible new method of treating unstable trochanteric femoral fractures. This may be the solution to prevent excessive collapse of the fracture with the resultant poor function and persisting pain noted in the literature. Two converging locked proximal screws seem to provide stable fixation in 31.A2 femoral fractures and produce as good a result as the use of traditional sliding screws. The role of converging locked proximal screws in unstable trochanteric fractures requires further evaluation.
The major limitations of pathogen-directed therapies are the emergence of drug-resistance and their narrow spectrum of coverage. A recently applied approach directs therapies against host proteins exploited by pathogens in order to circumvent these limitations. However, host-oriented drugs leave the pathogens unaffected and may result in continued pathogen dissemination. In this study we aimed to discover drugs that could simultaneously cross-inhibit pathogenic agents, as well as the host proteins that mediate their lethality. We observed that many pathogenic and host-assisting proteins belong to the same functional class. In doing so we targeted a protease component of anthrax toxin as well as host proteases exploited by this toxin. We identified two approved drugs, ascorbic acid 6-palmitate and salmon sperm protamine, that effectively inhibited anthrax cytotoxic protease and demonstrated that they also block proteolytic activities of host furin, cathepsin B, and caspases that mediate toxin’s lethality in cells. We demonstrated that these drugs are broad-spectrum and reduce cellular sensitivity to other bacterial toxins that require the same host proteases. This approach should be generally applicable to the discovery of simultaneous pathogen and host-targeting inhibitors of many additional pathogenic agents.
Results from the current survey show that patients' response to neoCTRT predicted by the multi-analyte IHC-based test has a significant influence on the decision-making process in the clinic. Nearly twice as many surgeons stated an intention to change strategy with the knowledge that the patient is likely to have extreme resistance to planned treatments than when one is a potential responder. The current survey study is limited by its 'intended use' nature, therefore does not reflect physicians' real action in the clinic upon implementation of this test. However, survey results strongly suggest that use of the IHC-based predictive test is of great interest to physicians, and would likely contribute to more individualized treatment for patients with distinct sensitivity to neoCTRT.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.