Alleviating the burden of tuberculosis (TB) requires an understanding of the genetic basis that determines the emergence of drug-resistant mutants. PA-824 (pretomanid) is a bicyclic nitroimidazole class compound presently undergoing the phase III STAND clinical trial, despite lacking identifiable genetic markers for drug-specific resistant Mycobacterium tuberculosis. In the present study, we aimed to characterize the genetic polymorphisms of spontaneously generated PA-824-resistant mutant strains by surveying drug metabolism genes for potential mutations. Of the 183 independently selected PA-824-resistant M. tuberculosis mutants, 83% harbored a single mutation in one of five nonessential genes associated with either PA-824 prodrug activation (ddn, 29%; fgd1, 7%) or the tangential F 420 biosynthetic pathway (fbiA, 19%; fbiB, 2%; fbiC, 26%). Crystal structure analysis indicated that identified mutations were specifically located within the protein catalytic domain that would hinder the activity of the enzymes required for prodrug activation. This systematic analysis conducted of genotypes resistant to PA-824 may contribute to future efforts in monitoring clinical strain susceptibility with this new drug therapy.T uberculosis (TB) remains a major global health concern, with Ͼ8 million new cases and 1.8 million deaths occurring annually (WHO). This pandemic is exacerbated by the pervasive spread of multidrug-resistant (MDR)-TB that challenges clinicians to fight a disease with a limited arsenal of resources. The bicyclic 4-nitroimidazole chemotype has yielded two promising candidates, delamanid (OPC67683) and pretomanid (PA-824), which actively inhibit both nonreplicating and rapidly growing bacilli under aerobic and anaerobic conditions (1). Both drugs are undergoing clinical evaluation and FDA approval is pending for the treatment of MDR-TB. In 2013, delamanid received conditional marketing authorization by the European Medicines Agency (EMA) for use in adult patients deprived of other treatment options (2). PA-824 is in the phase III STAND clinical trial, and at this stage of the development pipeline, it would be beneficial to monitor the genetic basis of resistant clinical strains as they emerge in the wake of future implementation into a treatment protocol.Bicyclic 4-nitroimidazoles are prodrugs that require metabolic activation by a deazaflavin (cofactor F 420 )-dependent nitroreductase (Ddn) (3). Ddn (Rv3547) converts the prodrugs into three primary metabolites, a des-nitroimidazole and two unstable byproducts (4). Ddn is likely a membrane-bound protein (5) that is involved in a protective mechanism under oxidative stress (6). The major mechanism of action of nitroimidazole in active disease under aerobic conditions is to hinder the formation of mycolic acids, and under anaerobic conditions, the mechanism involves the induction of respiratory poisoning (4, 7). By inhibiting the formation of ketomycolates, a class of mycolic acids, nitroimidazole interferes with Mycobacterium tuberculosis cell wall formation, ...

The failure in effective cancer treatment is thought to be attributed to a subpopulation of tumor cells with stem cell-like properties. These cancer stem cells (CSCs) are intimately linked to tumor initiation, heterogeneity, maintenance, recurrence and metastasis. Increasing evidence supports the view that a tight redox regulation is crucial for CSC proliferation, tumorigenicity, therapy resistance and metastasis in many cancer types. Since the distinct metabolic and epigenetic states of CSCs may influence ROS levels, and hence their malignancy, ROS modulating agents hold promise in their utility as anti-CSC agents that may improve the durability of current cancer treatments. This review will focus on (i) how ROS levels are regulated for CSCs to elicit their hallmark features; (ii) the link between ROS and metabolic plasticity of CSCs; and (iii) how ROS may interface with epigenetics that would enable CSCs to thrive in a stressful tumor microenvironment and survive therapeutic insults.

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The delivery of imaging agents to brain tumor sites has been a longstanding hindrance, because of the presence of blood-brain barriers (BBB) and the complex brain tumor microenvironment. The living cell-based delivery system has shown tantalizing prospects for therapeutic applications targeting oncological diseases. Herein, we design a lipid-decorated molecular photoacoustic contrast agent TFML, which can effectively label harvested live neutrophils without affecting the activation and transmigration functions. After labeling neutrophils with TFML probes, TFML-labeled neutrophil (TFML-NE) was adoptively transferred into the recipient body and demonstrated strong PA signals, good brain tumor-targeting capability, and was applied for mice glioblastoma multiforme (GBM) detection. The successful development of TFML probes for neutrophil labeling and brain tumor targeting PAI presents a promising prospect for neutrophil-based nanotherapeutics studies.