New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

BackgroundTransposable elements are major evolutionary forces which can cause new genome structure and species diversification. The role of transposable elements in the expansion of nucleotide-binding and leucine-rich-repeat proteins (NLRs), the major disease-resistance gene families, has been unexplored in plants.ResultsWe report two high-quality de novo genomes (Capsicum baccatum and C. chinense) and an improved reference genome (C. annuum) for peppers. Dynamic genome rearrangements involving translocations among chromosomes 3, 5, and 9 were detected in comparison between C. baccatum and the two other peppers. The amplification of athila LTR-retrotransposons, members of the gypsy superfamily, led to genome expansion in C. baccatum. In-depth genome-wide comparison of genes and repeats unveiled that the copy numbers of NLRs were greatly increased by LTR-retrotransposon-mediated retroduplication. Moreover, retroduplicated NLRs are abundant across the angiosperms and, in most cases, are lineage-specific.ConclusionsOur study reveals that retroduplication has played key roles for the massive emergence of NLR genes including functional disease-resistance genes in pepper plants.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1341-9) contains supplementary material, which is available to authorized users.

Nonhost resistance, a resistance of plant species against all nonadapted pathogens, is considered the most durable and efficient immune system of plants but yet remains elusive. The underlying mechanism of nonhost resistance has been investigated at multiple levels of plant defense for several decades. In this review, we have comprehensively surveyed the latest literature on nonhost resistance in terms of preinvasion, metabolic defense, pattern-triggered immunity, effector-triggered immunity, defense signaling, and possible application in crop protection. Overall, we summarize the current understanding of nonhost resistance mechanisms. Pre- and postinvasion is not much deviated from the knowledge on host resistance, except for a few specific cases. Further insights on the roles of the pattern recognition receptor gene family, multiple interactions between effectors from nonadapted pathogen and plant factors, and plant secondary metabolites in host range determination could expand our knowledge on nonhost resistance and provide efficient tools for future crop protection using combinational biotechnology approaches. [Formula: see text] Copyright © 2017 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Plants possess hundreds of intracellular immune receptors encoding nucleotide-binding domain and leucine-rich repeat (NLR) proteins. Autoactive NLRs, some cases a specific domain of NLR, induce plant cell death in the absence of pathogen infection. In this study, we identified a group of NLRs (ANLs; ancient and autonomous NLRs) carrying autoactive coiled-coil (CC A) domains in pepper (Capsicum annuum L.) by genome-wide transient expression analysis. The CC A-mediated cell death mimics hypersensitive cell death triggered by interaction between NLR and pathogen effectors. Sequence alignment and mutagenesis analyses revealed that the intact α1 helix of CC A is critical for both CC A-and ANL-mediated cell death. The cell death induced by CC A does not require NRG1/ADR1 or NRC type helper NLRs, suggesting ANLs may function as singleton NLRs. We also found that CC A localize in the plasma membrane as Arabidopsis singleton NLR ZAR1. Extended studies revealed that autoactive CC A s are well conserved in other Solanaceae plants as well as a monocot plant, rice. Further phylogenetic analyses revealed that ANLs are present in all tested seed plants (spermatophytes). Our studies not only uncover the autonomous NLR clade in plants but also provide powerful resources for dissecting the underlying molecular mechanism of NLR-mediated cell death in plant.

The hypersensitive response (HR) is a robust immune response mediated by nucleotidebinding, leucine-rich repeat receptors (NLRs). However, the early molecular event that links activated NLRs to cell death is unclear.Here, we demonstrate that NLRs target plasma membrane H + -ATPases (PMAs) that generate electrochemical potential, an essential component of living cells, across the plasma membrane. CC A 309, an autoactive N-terminal domain of a coiled-coil NLR (CNL) in pepper, is associated with PMAs. Silencing or overexpression of PMAs reversibly affects cell death induced by CC A 309 in Nicotiana benthamiana.CC A 309-induced extracellular alkalization causes plasma membrane depolarization, followed by cell death. Coimmunoprecipitation analyses suggest that CC A 309 inhibits PMA activation by preoccupying the dephosphorylated penultimate threonine residue of PMA. Moreover, pharmacological experiments using fusicoccin, an irreversible PMA activator, showed that inhibition of PMAs contributes to CNL-type (but not Toll interleukin-1 receptor NLR-type) resistance protein-induced cell death.We suggest PMAs as primary targets of plasma membrane-associated CNLs leading to HRassociated cell death by disturbing the electrochemical gradient across the membrane. These results provide new insight into NLR-mediated cell death in plants, as well as innate immunity in higher eukaryotes.