Cavomycins A-C, Linear Oligomer Depsipeptides from an Annelid-Associated Streptomyces cavourensis.

Three unique linear oligomeric depsipeptides, designated as cavomycins A-C (1-3), were identified from Streptomyces cavourensis, a gut bacterium associated with the annelid Paraleonnates uschakovi. The structures of these depsipeptides were determined through a combination of spectroscopic methods and chemical derivatization techniques, including methanolysis, the modified Mosher's method, advanced Marfey's methods, and phenylglycine methyl ester derivatization. The unique dipeptidyl residue arrangements in compounds 1-3 indicate that they are not degradation products of valinomycin. Compound 2 and its methylation derivative 2a exhibited antiproliferative activity against PANC-1 pancreatic cancer cells with IC50 values of 1.2 and 1.7 µM, respectively.

Proximal Femur Salvage in Revision Knee Arthroplasty Due to Oncologic Indications: Long-term Results of Onlay and Overlapping Allograft in Revision Surgeries.

Background: Mechanical failures of tumor endoprosthesis in the distal femur usually require revision surgery. We investigated if the proximal femur host bone can be salvaged by onlay and overlapping allograft in revision surgeries due to aseptic loosening and stem fractures. Methods: We retrospectively reviewed 18 patients (7 men and 11 women) with osteosarcoma around the knee. The entire cohort was classified into three subgroups (no bone graft: 6, onlay allograft: 7, and overlapping allograft: 5) according to our treatment strategy. Results: The median interval from the initial surgery to the revision was 94.5 months (range, 21-219 months), and the median follow-up period from the revision surgery was 88.0 months (range, 24-179 months). At the last follow-up, 9 of the 18 patients maintained their endoprostheses, and the 5-year prosthesis survival rate was 57.9%. Limb survival was 100%. Five-year prosthesis survival rate was 66.7% in the no bone graft group, 85.7% in the onlay allograft group while 30.0% in the overlapping allograft group. In the no bone graft group and onlay allograft group, 66.7% (4/6) and 57.1% (4/7) maintained their revision prostheses while no prostheses survived in the overlapping allograft group. Recurrent stem loosening was observed in 14.2% (1/7) and 60.0% (3/5) of the onlay allograft and overlapping allograft groups, respectively, despite allograft bone union. The complication rate was 66.7% (12/18) in the entire cohort. The most common type of complication was infection (n = 6), followed by aseptic loosening (n = 4) and mechanical failure (n = 2). Conclusions: This study indicates that onlay allograft can be used as a supportive method in revising failed endoprosthesis if the extent of host bone destruction is extensive. However, applying overlapping allograft to secure bone stock showed a high rate of mechanical failures and infection in the long term. Future studies with a larger cohort are necessary to assess the prognostic factors for the higher complication rate in overlapping allograft and the need for overlapping allograft. Surveillance with consideration of the risk of anteromedial osteolysis in allograft and efforts for prevention of periprosthetic infection are essential.

Ankle Strategies for Step-Aside Movement during Straight Walking.

The step-aside movement, also known as the dodging step, is a common maneuver for avoiding obstacles while walking. However, differences in neural control mechanisms and ankle strategies compared to straight walking can pose a risk of falling. This study aimed to examine the differences in tibialis anterior (TA), peroneus longus (PL), and soleus (SOL) muscle contractions, foot center of pressure (CoP) displacement, and ground reaction force (GRF) generation between step-aside movement and straight walking to understand the mechanism behind step-aside movement during walking. Twenty healthy young male participants performed straight walking and step-aside movements at comfortable walking speeds. The participants' muscle contractions, CoP displacement, and GRF were measured. The results show significant greater bilateral ankle muscle contractions during the push and loading phases of step-aside movement than during straight walking. Moreover, the CoP displacement, GRF generation mechanism, and timing differed from those observed during straight walking. These findings provide valuable insights for rehabilitation professionals in the development of clinical decisions for populations at a risk of falls and lacking gait stability.

Discovery of a New Antibiotic Demethoxytetronasin Using a Dual-Sided Agar Plate Assay (DAPA).

For over a century, researchers have cultured microorganisms together on solid support─typically agar─in order to observe growth inhibition via antibiotic production. These simple bioassays have been critical to both academic researchers that study antibiotic production in microorganisms and to the pharmaceutical industry's global effort to discover drugs. Despite the utility of agar assays to researchers around the globe, several limitations have prevented their widespread adoption in advanced high-throughput compound discovery and dereplication campaigns. To address a list of specific shortcomings, we developed the dual-sided agar plate assay (DAPA), which exists in a 96-well plate format, allows microorganisms to compete through opposing sides of a solid support in individual wells, is amenable to high-throughput screening and automation, is reusable, and is low-cost. Herein, we validate the use of DAPA as a tool for drug discovery and show its utility to discover new antibiotic natural products. From the screening of 217 bacterial isolates on multiple nutrient media against 3 pathogens, 55 hits were observed, 9 known antibiotics were dereplicated directly from agar plugs, and a new antibiotic, demethoxytetronasin (1), was isolated from a Streptomyces sp. These results demonstrate that DAPA is an effective, accessible, and low-cost tool to screen, dereplicate, and prioritize bacteria directly from solid support in the front end of antibiotic discovery pipelines.

Ankle strategies for step-aside movement during quiet standing.

The mediolateral ankle strategy plays a crucial role in providing ankle stability in ground obstacle-avoidance behavior. This is achieved by changing basic walking patterns according to the characteristics of the obstacle. In daily life, it is more common to use step-aside movement (i.e., dodging step) for collision avoidance rather than side-stepping (i.e., widening standing base) when encountering an approaching pedestrian or bicycle. While studies have been conducted on the mediolateral ankle strategy contribution in obstacle avoidance using side-stepping, knowledge of step-aside movement is still inadequate. Therefore, we conducted an electromyography (EMG) analysis on the tibialis anterior (TA), peroneus longus (PL), and soleus (SOL) muscles, as well as measured center of pressure (CoP) displacement, and vertical ground reaction force (vGRF) of the standing leg, in order to understand the role of ankle muscles in step-aside movement during quiet standing. Fifteen healthy young men repeated twelve step-aside movements in both left and right directions. A Bayesian one-sample t-test was used to determine the sufficient step and participant counts. Multiple linear regression analysis was used to investigate the correlation between the muscle activity and CoP displacement or vGRF. The regression coefficients (ß) of the left push phase and the right loading phase were tested against zero using a Bayesian one-sample t-test to identify the correlation between independent and dependent variables. We used the one-dimensional statistical parametric mapping (SPM1d) method to analyze the differences between and within the groups of EMG data based on the continuous time series. The results showed that the PL displayed a substantial contribution to the mediolateral ankle strategy during the push phase of step-aside movement, and also contributed to maintaining ankle stability during the loading phase. This suggested that screening for PL weakness and providing appropriate interventions and/or training approaches is especially critical for populations with walking stability problems.

Protective role of colitis in inflammatory arthritis via propionate-producing Bacteroides in the gut.

Objectives: To investigate whether and how inflammatory disease in the intestine influences the development of arthritis, considering that organ-to-organ communication is associated with many physiological and pathological events. Methods: First, mice were given drinking water containing dextran sodium sulfate (DSS) and then subjected to inflammatory arthritis. We compared the phenotypic symptoms between the cohoused and separately-housed mice. Next, donor mice were divided into DSS-treated and untreated groups and then cohoused with recipient mice. Arthritis was then induced in the recipients. The fecal microbiome was analyzed by 16S rRNA amplicon sequencing. We obtained type strains of the candidate bacteria and generated propionate-deficient mutant bacteria. Short-chain fatty acids were measured in the bacterial culture supernatant, serum, feces, and cecum contents using gas chromatography-mass spectrometry. Mice fed with candidate and mutant bacteria were subjected to inflammatory arthritis. Results: Contrary to expectations, the mice treated with DSS exhibited fewer symptoms of inflammatory arthritis. Intriguingly, the gut microbiota contributes, at least in part, to the improvement of colitis-mediated arthritis. Among the altered microorganisms, Bacteroides vulgatus and its higher taxonomic ranks were enriched in the DSS-treated mice. B. vulgatus, B. caccae, and B. thetaiotaomicron exerted anti-arthritic effects. Propionate production deficiency further prevented the protective effect of B. thetaiotaomicron on arthritis. Conclusions: We suggest a novel relationship between the gut and joints and an important role of the gut microbiota as communicators. Moreover, the propionate-producing Bacteroides species examined in this study may be a potential candidate for developing effective treatments for inflammatory arthritis.

Identification of the inhibitory mechanism of ecumicin and rufomycin 4-7 on the proteolytic activity of Mycobacterium tuberculosis ClpC1/ClpP1/ClpP2 complex.

Ecumicin and rufomycin 4-7 disrupt protein homeostasis in Mycobacterium tuberculosis by inhibiting the proteolytic activity of the ClpC1/ClpP1/ClpP2 complex. Although these compounds target ClpC1, their effects on the ATPase activity of ClpC1 and proteolytic activity of ClpC1/ClpP1/ClpP2 vary. Herein, we explored the ClpC1 molecular dynamics with these compounds through fluorescence correlation spectroscopy. The effect of these compounds on the ATPase activity of ClpC1-cys, the recombinant protein for fluorescence labeling, and proteolytic activity of ClpC1-cys/ClpP1/ClpP2 were identical to those of native ClpC1, whereas the intermolecular dynamics of fluorescence-labelled ClpC1 were different. Treatment with up to 1 nM ecumicin increased the population of slower diffused ClpC1 components compared with ClpC1 without ecumicin. However, this population was considerably reduced when treated with 10 nM ecumicin. Rufomycin 4-7 treatment resulted in a slower diffused component of ClpC1, and the portion of this component increased in a concentration-dependent manner. Ecumicin can generate an abnormal ClpC1 component, which cannot form normal ClpC1/ClpP1/ClpP2, via two different modes. Rufomycin 4-7 only generates slower diffused ClpC1 component that is inadequate to form normal ClpC1/ClpP1/ClpP2. Overall, we demonstrate that ecumicin and rufomycin 4-7 use different action mechanisms to generate abnormal ClpC1 components that cannot couple with ClpP1/ClpP2.

Dimensional Control of Highly Anisotropic and Transparent Conductive Coordination Polymers for Solution-Processable Large-Scale 2D Sheets.

Controlling the dimensional aspect of conductive coordination polymers is currently a key scientific interest. Herein, solution-based dimension control strategies are proposed for copper chloride thiourea (CuCl-TU) coordination polymers that enable centimeter-scale, 2D nanosheet formation for use as transparent electrodes. Despite the wide bandgap of CuCl-TU polymers (4.33 eV), through polaron-mediated electron transfer, the electrical conductivity of the 2D sheet at room temperature is able to reach 4.45 S cm-1 without intentional doping. This leads to a highly anisotropic electronic conductivity of up to the order of ≈103 differences, depending on the material orientation. Furthermore, by substituting alternative thiourea candidates, it is demonstrated that it is possible to predesign CuCl-TU structures with the desired functionality, stability, and porosity through dimensional control. These findings provide a blueprint to design next-generation transparent conducting materials that can operate at room temperature, thereby expanding their applicability to different fields.

New Rufomycins from Streptomyces atratus MJM3502 Expand Anti-Mycobacterium tuberculosis Structure-Activity Relationships.

Four new rufomycins, compounds 1-4, named rufomycins 56, 57, 58, and 61, respectively, exhibiting new skeletal features, were obtained from Streptomyces atratus strain MJM3502 and were fully characterized. Compounds 1 and 2 possess a 4-imidazolidinone ring not previously encountered in this family of cyclopeptides, thereby resulting in a [5,17] bicyclic framework. The in vitro anti-Mycobacterium tuberculosis potency of compounds 3 and 4 is remarkable, with minimum inhibitory concentration values of 8.5 and 130 nM, respectively.

Syntheses and studies of deuterated Imdiazo[1,2-a]pyridine-3-carboxamides with potent anti-tuberculosis activity and improved metabolic properties.

The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis (Mtb) as exemplified by clinical candidate Telacebec (Q203). These compounds target mycobacterial respiration through inhibition of the QcrB subunit of cytochrome bc1:aa3 super complex resulting in bacteriostatic efficacy in vivo. Our labs have had a long-standing interest in the design and development of IAPs. However, some of these compounds suffer from short in vivo half-lives, requiring multiple daily dosing or the addition of a cytochrome P450 inhibitor for murine efficacy evaluations. Deuteration has been shown to decrease metabolism as the C-D bond is stronger than the CH bond. Herein we describe our efforts on design and synthesis of potent deuterated IAPs and the effect that deuteration has upon metabolism through microsomal stability studies.

Genetic mutation spectrum of pantothenate kinase-associated neurodegeneration expanded by breakpoint sequencing in pantothenate kinase 2 gene.

BACKGROUND: Neurodegeneration with brain iron accumulation describes a group of rare heterogeneous progressive neurodegenerative disorders characterized by excessive iron accumulation in the basal ganglia region. Pantothenate kinase-associated neurodegeneration (PKAN) is a major form of this disease. RESULTS: A total of 7 unrelated patients were diagnosed with PKAN in a single tertiary center from August 2009 to February 2018. Ten variants in PANK2 including three novel sequence variants and one large exonic deletion were detected. Sequencing of the breakpoint was performed to predict the mechanism of large deletion and AluSx3 and AluSz6 were found with approximately 97.3% sequence homology. CONCLUSION: The findings support the disease-causing role of PANK2 and indicate the possibility that exonic deletion of PANK2 found in PKAN is mediated through Alu-mediated homologous recombination.

A mucin-responsive hybrid two-component system controls Bacteroides thetaiotaomicron colonization and gut homeostasis.

The mammalian intestinal tract contains trillions of bacteria. However, the genetic factors that allow gut symbiotic bacteria to occupy intestinal niches remain poorly understood. Here, we identified genetic determinants required for Bacteroides thetaiotaomicron colonization in the gut using transposon sequencing analysis. Transposon insertion in BT2391, which encodes a hybrid two-component system, increased the competitive fitness of B. thetaiotaomicron. The BT2391 mutant showed a growth advantage in a mucin-dependent manner and had an increased ability to adhere to mucus-producing cell lines. The increased competitive advantage of the BT2391 mutant was dependent on the BT2392-2395 locus containing susCD homologs. Deletion of BT2391 led to changes in the expression levels of B. thetaiotaomicron genes during gut colonization. However, colonization of the BT2391 mutant promoted DSS colitis in low-fiber diet-fed mice. These results indicate that BT2391 contributes to a sustainable symbiotic relationship by maintaining a balance between mucosal colonization and gut homeostasis.

The human symbiont Bacteroides thetaiotaomicron promotes diet-induced obesity by regulating host lipid metabolism.

The gut microbiome plays an important role in lipid metabolism. Consumption of a high-fat diet (HFD) alters the bacterial communities in the gut, leading to metabolic disorders. Several bacterial species have been associated with diet-induced obesity, nonalcoholic fatty liver disease, and metabolic syndrome. However, the mechanisms underlying the control of lipid metabolism by symbiotic bacteria remain elusive. Here, we show that the human symbiont Bacteroides thetaiotaomicron aggravates metabolic disorders by promoting lipid digestion and absorption. Administration of B. thetaiotaomicron to HFD-fed mice promoted weight gain, elevated fasting glucose levels, and impaired glucose tolerance. Furthermore, B. thetaiotaomicron treatment upregulated the gene expression of the fatty acid transporter and increased fatty acid accumulation in the liver. B. thetaiotaomicron inhibits expression of the gene encoding a lipoprotein lipase inhibitor, angiopoietin-like protein 4 (ANGPTL4), thereby increasing lipase activity in the small intestine. In particular, we found that B. thetaiotaomicron induced the expression of hepcidin, the master regulator of iron metabolism and an antimicrobial peptide, in the liver. Hepcidin treatment resulted in a decrease in ANGPTL4 expression in Caco-2 cells, whereas treatment with an iron chelator restored ANGPTL4 expression in hepcidin-treated cells. These results indicate that B. thetaiotaomicron-mediated regulation of iron storage in intestinal epithelial cells may contribute to increased fat deposition and impaired glucose tolerance in HFD-fed mice.

Anti-Microbial Activity of Aliphatic Alcohols from Chinese Black Cardamom (Amomum tsao-ko) against Mycobacterium tuberculosis H37Rv

The fruits of Amomun tsao-ko (Chinese black cardamom; Zingiberaceae) contain an abundance of essential oils, which have previously demonstrated significant antimicrobial activity. In our preliminary search for natural anti-tuberculosis agents, an acetone extract of A. tsao-ko (AAE) exhibited strong antibacterial activity against Mycobacterium tuberculosis H37Rv. Therefore, the aim of this study was to find the principal compounds in an AAE against M. tuberculosis. Nine aliphatic compounds (1−9) including a new compound (1, tsaokol B) and a new natural unsaturated aliphatic diester (6), together with three acyclic terpenoids (10−12), were isolated from an AAE by repetitive chromatography. The structures of the isolates were determined by spectroscopic data analysis. All isolates were evaluated for activity against M. tuberculosis H37Rv. Isolated compounds 1−6, and 11 had MICs ranging from 0.6−89 µg/mL. In contrast, compounds 7 to 10, and 12 had MICs that were >100 µg/mL. Tsaokol A (3) was the most active compound with MICs of 0.6 µg/mL and 1.4 µg/mL, respectively, against replicating and nonreplicating M. tuberculosis. These results are the first to illustrate the potency of tsaokol A (3) as a natural drug candidate with good selectivity for treating tuberculosis.

Rufomycins or Ilamycins: Naming Clarifications and Definitive Structural Assignments.

Rufomycin and ilamycin are synonymous for the same class of cyclopeptides, currently encompassing 33 structurally characterized isolates and 9 semisynthetic derivatives. Elucidation of new structures prioritized the consolidation of the names and established the structures of four diastereoisomeric rufomycins with a 2-piperidinone, named rufomycins 4-7, including full 1H/13C NMR assignments. The characteristic HSQC cross-peak for the CH-5, the hemiaminal carbon in amino acid #5, allows assignment of the stereocenters C-4 and C-5 within this ring. Semisynthetic derivatives (rufomycinSS 1, 2, and 3) were prepared from a rufomycins 4 and 6 mixture to validate the structural assignments. Based on the X-ray crystal structures of rufomycins 2 and 4, considering the NMR differences of rufomycins 7 vs 4-6 compared to rufomycinSS 1 vs 2 and 3, and taking into account that two major conformers, A and B, occur in both rufomycinSS 2 and 3, structural modeling was pursued. Collectively, this paper discusses the NMR spectroscopic differences of the stereoisomers and their possible 3D conformers and correlates these with the anti-Mycobacterium tuberculosis activity. In addition, a look at the history prioritizes names and numbering schemes for this group of antibiotics and leads to consolidated nomenclature for all currently known members, natural and semisynthetic derivatives, and serves to accommodate future discoveries.

Incidence and treatment outcomes of ovarian sarcoma compared to epithelial ovarian cancer from the national cancer registry.

PURPOSE: To investigate the incidence and survival outcomes of primary ovarian sarcoma compared to those of epithelial ovarian cancer. METHODS: Data on primary ovarian sarcoma patients (n = 1361) and epithelial ovarian cancer patients (n = 30,366) between 1999 and 2017 were obtained from the Korea Central Cancer Registry, and their respective age-standardized incidence rate (ASR) and relative survival rate were calculated and compared. RESULTS: Based on the ASR, the incidence of epithelial ovarian cancer was 4.75 per 100,000 women, while that of primary ovarian sarcoma was 0.22 per 100,000 women. The ASR ratio was 21.94 without significant change of ASR during the study period. Primary ovarian sarcoma had a better survival curve compared with epithelial ovarian cancer, though the difference was not statistically significant (5 yr overall survival 64.0% vs. 61.5%; p = 0.6030). In addition, among the pure sarcomas, the fibrosarcoma histologic subtype showed the best overall survival, and that of liposarcomas and stromal cell sarcoma were behind that (5 yr overall survival 85.0%, 76.7%, and 72.7%; p < 0.0001). CONCLUSIONS: The incidence of primary ovarian sarcoma is quite low, with an ASR of 0.22/100,000 during the last 20 years. There were no significant differences between survival rates of primary ovarian sarcoma and epithelial ovarian cancer.

Rufomycin Exhibits Dual Effects Against Mycobacterium abscessus Infection by Inducing Host Defense and Antimicrobial Activities.

Nontuberculous mycobacterial pulmonary infection is often aggravated due to antibiotic resistance issues. There is a need for development of new drugs inducing both host immune responses and antimicrobial activities. This study shows that the rufomycins 4/5/6/7 (Rufomycin 4-7), which targets ClpC1 as a subunit of caseinolytic protein complex ClpC1/ClpP1/ClpP2 of mycobacteria, exhibits a dual effect in host innate defense and in vivo antimicrobial activities against a rough morphotype of Mycobacterium abscessus (Mabs-R), a clinically severe morphotype that causes hyperinflammation. Rufomycin 4-7 treatment showed antimicrobial effects against Mabs pulmonary infection in vivo and in macrophages. In addition, Rufomycin 4-7 significantly decreased inflammation, but enhanced the autophagy/lysosomal genes through upregulation of the nuclear translocation of transcription factor EB (TFEB). Furthermore, Rufomycin 4-7 treatment effectively inhibited mitochondrial damage and oxidative stresses in macrophages during Mabs-R infection. Collectively, Rufomycin 4-7-mediated dual effects inducing both antimicrobial activities and host immune defense might confer an advantage to treatment against Mabs-R infection.

In Vitro Profiling of Antitubercular Compounds by Rapid, Efficient, and Nondestructive Assays Using Autoluminescent Mycobacterium tuberculosis.

Anti-infective drug discovery is greatly facilitated by the availability of in vitro assays that are more proficient at predicting the preclinical success of screening hits. Tuberculosis (TB) drug discovery is hindered by the relatively slow growth rate of Mycobacterium tuberculosis and the use of whole-cell-based in vitro assays that are inherently time-consuming, and for these reasons, rapid, noninvasive bioluminescence-based assays have been widely used in anti-TB drug discovery and development. In this study, in vitro assays that employ autoluminescent M. tuberculosis were optimized to determine MIC, minimum bactericidal concentration (MBC), time-kill curves, activity against macrophage internalized M. tuberculosis (90% effective concentration [EC90]), and postantibiotic effect (PAE) to provide rapid and dynamic biological information. Standardization of the luminescence-based MIC, MBC, time-kill, EC90, and PAE assays was accomplished by comparing results of established TB drugs and two ClpC1-targeting TB leads, ecumicin and rufomycin, to those obtained from conventional assays and/or to previous studies. Cumulatively, the use of the various streamlined luminescence-based in vitro assays has reduced the time for comprehensive in vitro profiling (MIC, MBC, time-kill, EC90, and PAE) by 2 months. The luminescence-based in vitro MBC and EC90 assays yield time and concentration-dependent kill information that can be used for pharmacokinetic-pharmacodynamic (PK-PD) modeling. The MBC and EC90 time-kill graphs revealed a significantly more rapid bactericidal activity for ecumicin than rufomycin. The PAEs of both ecumicin and rufomycin were comparable to that of the first-line TB drug rifampin. The optimization of several nondestructive, luminescence-based TB assays facilitates the in vitro profiling of TB drug leads in an efficient manner.

Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions.

The biological processes related to protein homeostasis in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, have recently been established as critical pathways for therapeutic intervention. Proteins of particular interest are ClpC1 and the ClpC1-ClpP1-ClpP2 proteasome complex. The structure of the potent antituberculosis macrocyclic depsipeptide ecumicin complexed with the N-terminal domain of ClpC1 (ClpC1-NTD) is presented here. Crystals of the ClpC1-NTD-ecumicin complex were monoclinic (unit-cell parameters a = 80.0, b = 130.0, c = 112.0 Å, ß = 90.07°; space group P21; 12 complexes per asymmetric unit) and diffracted to 2.5 Šresolution. The structure was solved by molecular replacement using the self-rotation function to resolve space-group ambiguities. The new structure of the ecumicin complex showed a unique 1:2 (target:ligand) stoichiometry exploiting the intramolecular dyad in the α-helical fold of the target N-terminal domain. The structure of the ecumicin complex unveiled extensive interactions in the uniquely extended N-terminus, a critical binding site for the known cyclopeptide complexes. This structure, in comparison with the previously reported rufomycin I complex, revealed unique features that could be relevant for understanding the mechanism of action of these potential antituberculosis drug leads. Comparison of the ecumicin complex and the ClpC1-NTD-L92S/L96P double-mutant structure with the available structures of rufomycin I and cyclomarin A complexes revealed a range of conformational changes available to this small N-terminal helical domain and the minor helical alterations involved in the antibiotic-resistance mechanism. The different modes of binding and structural alterations could be related to distinct modes of action.

New tuberculosis drug targets, their inhibitors, and potential therapeutic impact.

The current tuberculosis (TB) predicament poses numerous challenges and therefore every incremental scientific work and all positive socio-political engagements, are steps taken in the right direction to eradicate TB. Progression of the late stage TB-drug pipeline into the clinics is an immediate deliverable of this global effort. At the same time, fueling basic research and pursuing early discovery work must be sustained to maintain a healthy TB-drug pipeline. This review encompasses a broad analysis of chemotherapeutic strategies that target the DNA replication, protein synthesis, cell wall biosynthesis, energy metabolism and proteolysis of Mycobacterium tuberculosis (Mtb). It includes a status check of the current TB-drug pipeline with a focus on the associated biology, emerging targets, and their promising chemical inhibitors. Potential synergies and/or gaps within or across different chemotherapeutic strategies are systematically reviewed as well.