Drug design and identification of potent leads against Mycobacterium tuberculosis thymidine monophosphate kinase

Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases impeding DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), which is essential to DNA replication, was selected as a promising target for the design of new inhibitors. This review describes stepwise modifications of the TMPKmt substrate, guided by the feedback of enzyme assays and crystallographic analysis to afford potent enzyme inhibitors some of which also exhibited antitubercular activity. More importantly, several of the reported thymidine analogues provided a deeper understanding of the structure and catalytic mechanism of this intriguing enzyme

Synthetic fosmidomycin analogues with altered chelating moieties do not inhibit 1-deoxy-D-xylulose 5-phosphate reductoisomerase or Plasmodium falciparum growth in vitro

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or the Plasmodia. This study further underlines the importance of the hydroxamate functionality and illustrates that identifying effective alternative bidentate ligands for this target enzyme is challenging

Al-2 quorum-sensing inhibitors affect the starvation response and reduce virulence in several <i>Vibrio</i> species, most likely by interfering with LuxPQ

The increase of disease outbreaks caused by Vibrio species in aquatic organisms as well as in humans, together with the emergence of antibiotic resistance in Vibrio species, has led to a growing interest in alternative disease control measures. Quorum sensing (QS) is a mechanism for regulating microbial gene expression in a cell density-dependent way. While there is good evidence for the involvement of auto-inducer 2 (AI-2)-based interspecies QS in the control of virulence in multiple Vibrio species, only few inhibitors of this system are known. From the screening of a small panel of nucleoside analogues for their ability to disturb AI-2-based QS, an adenosine derivative with a p-methoxyphenylpropionamide moiety at C-3′ emerged as a promising hit. Its mechanism of inhibition was elucidated by measuring the effect on bioluminescence in a series of Vibrio harveyi AI-2 QS mutants. Our results indicate that this compound, as well as a truncated analogue lacking the adenine base, block AI-2-based QS without interfering with bacterial growth. The active compounds affected neither the bioluminescence system as such nor the production of AI-2, but most likely interfered with the signal transduction pathway at the level of LuxPQ in V. harveyi. The most active nucleoside analogue (designated LMC-21) was found to reduce the Vibrio species starvation response, to affect biofilm formation in Vibrio anguillarum, Vibrio vulnificus and Vibrio cholerae, to reduce pigment and protease production in V. anguillarum, and to protect gnotobiotic Artemia from V. harveyi-induced mortality

Learning curves of open and endoscopic fetal spina bifida closure: a systematic review and meta-analysis

OBJECTIVES: The Management Of Myelomeningocele Study (MOMS) trial demonstrated the safety and efficacy of open fetal surgery for spina bifida (SB). Recently developed alternative techniques may reduce maternal risks yet should do without compromising on fetal neuroprotective effects. We aimed to assess the learning curve of different fetal SB closure techniques. METHODS: We searched Medline, Web of Science, Embase, Scopus and Cochrane databases and the grey literature to identify relevant articles without language restriction from January 1980 until October 2018. We systematically reviewed and selected studies reporting all consecutive procedures and with a postnatal follow-up ≥12 months. They also had to report outcome variables necessary to measure the learning curve defined by fetal safety and efficacy. Two independent authors retrieved the data, assessed the quality of the studies and categorized observations into blocks of 30 patients. For meta-analysis, data were pooled using a random-effect model when heterogeneous. To measure the learning curve, we used two complementary methods. With the group splitting method, competency was defined when the procedure provided comparable results to the MOMS trial for 12 outcome variables representative for (1) the immediate surgical outcome, (2) short-term neonatal neuroprotection and (3) long-term neuroprotection at ≥12 months. Then, when the patients' raw data were available, we performed cumulative sum (CUSUM) analysis based on a composite binary outcome defining a successful surgery. It combined four clinically relevant variables for safety (fetal death within 7 days) and for efficacy (neuroprotection at birth). RESULTS: We included 17/6024 (0.3%) studies with low and moderate risks of bias. Fetal SB closure was performed via standard-hysterotomy (n=11), mini-hysterotomy (n=1) or fetoscopy [exteriorized-uterus single-layer (n=1), percutaneous single-layer (n=3) or percutaneous two-layer closure (n=1)]. Only outcomes for the standard-hysterotomy could be meta-analyzed. Overall, outcomes significantly improved with experience. Competency was reached after 35 consecutive cases for standard-hysterotomy and was predicted to be achieved after ≥57 cases for mini-hysterotomy and ≥56 for percutaneous two-layer fetoscopy. For percutaneous and uterus-exteriorized single-layer fetoscopy, competency was not respectively reached by cases 81 and 28 available for analysis. CONCLUSIONS: The number of cases operated correlates with the outcome of SB fetal closure and ranges from 35 cases for standard-hysterotomy to ≥56-57 cases for minimally invasive modifications. Our observations provide important information for institutions eager to establish a new fetal center, develop a new technique or train their team, and inform referring clinicians, potential patients and third-parties

The rationale of opportunistic bilateral salpingectomies (OBS) during benign gynaecological and obstetric surgery : a consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG)

Ovarian cancer (OC), is a disease difficult to diagnose in an early stage implicating a poor prognosis. The 5-year overall survival in Belgium has not changed in the last 18 years and remains 44 %. There is no effective screening method (secondary prevention) to detect ovarian cancer at an early stage. Primary prevention of ovarian cancer came in the picture through the paradigm shift that the fallopian tube is often the origin of ovarian cancer and not the ovary itself. Opportunistic bilateral salpingectomy (OBS) during benign gynaecological and obstetric surgery might have the potential to reduce the risk of ovarian cancer by as much as 65 %. Bilateral risk-reducing salpingectomy during a benign procedure is feasible, safe, appears to have no impact on the ovarian function and seems to be cost effective. The key question is whether we should wait for a RCT or implement OBS directly in our daily practice. Guidelines regarding OBS within our societies are therefore urgently needed. Our recommendation is to inform all women without a child wish, undergoing a benign gynaecological or obstetrical surgical procedure about the pro’s and the con’s of OBS and advise a bilateral salpingectomy. Furthermore, there is an urgent need for a prospective registry of OBS. The present article is the consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG) regarding OBS

Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors

[Abstract] The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order kth (Wk). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the Wk(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated Wk(i) values were used as inputs for different ANNs in order to discriminate correct node connectivity patterns from incorrect random patterns. The MIANN models obtained present good values of Sensitivity/Specificity (%): MRNs (78/78), IWDBNs (90/88), and SFLN (86/84). These preliminary results are very promising from the point of view of a first exploratory study and suggest that the use of these models could be extended to the high-throughput re-evaluation of connectivity in known complex networks (collation)