Abstract:A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection.
“…2 ). An important point is that the WGS strategies of screening for novel “drugable” classes of molecules and targets are easily compatible with natural product discovery programs and existing phenotypic high-throughput screening and thus can significantly improve and speed up current practical outcomes [ 13 , 35 , 108 , 148 ]. Fig 2 Schematic procedure of drug development based on genomic data, obtained by WGS …”
During the past two decades, the technological progress of whole-genome sequencing (WGS) had changed the fields of Environmental Microbiology and Biotechnology, and, currently, is changing the underlying principles, approaches, and fundamentals of Public Health, Epidemiology, Health Economics, and national productivity. Today’s WGS technologies are able to compete with conventional techniques in cost, speed, accuracy, and resolution for day-to-day control of infectious diseases and outbreaks in clinical laboratories and in long-term epidemiological investigations. WGS gives rise to an exciting future direction for personalized Genomic Epidemiology. One of the most vital and growing public health problems is the emerging and re-emerging of multidrug-resistant (MDR) bacterial infections in the communities and healthcare settings, reinforced by a decline in antimicrobial drug discovery. In recent years, retrospective analysis provided by WGS has had a great impact on the identification and tracking of MDR microorganisms in hospitals and communities. The obtained genomic data are also important for developing novel easy-to-use diagnostic assays for clinics, as well as for antibiotic and therapeutic development at both the personal and population levels. At present, this technology has been successfully applied as an addendum to the real-time diagnostic methods currently used in clinical laboratories. However, the significance of WGS for public health may increase if: (a) unified and user-friendly bioinformatics toolsets for easy data interpretation and management are established, and (b) standards for data validation and verification are developed. Herein, we review the current and future impact of this technology on diagnosis, prevention, treatment, and control of MDR infectious bacteria in clinics and on the global scale.
“…2 ). An important point is that the WGS strategies of screening for novel “drugable” classes of molecules and targets are easily compatible with natural product discovery programs and existing phenotypic high-throughput screening and thus can significantly improve and speed up current practical outcomes [ 13 , 35 , 108 , 148 ]. Fig 2 Schematic procedure of drug development based on genomic data, obtained by WGS …”
During the past two decades, the technological progress of whole-genome sequencing (WGS) had changed the fields of Environmental Microbiology and Biotechnology, and, currently, is changing the underlying principles, approaches, and fundamentals of Public Health, Epidemiology, Health Economics, and national productivity. Today’s WGS technologies are able to compete with conventional techniques in cost, speed, accuracy, and resolution for day-to-day control of infectious diseases and outbreaks in clinical laboratories and in long-term epidemiological investigations. WGS gives rise to an exciting future direction for personalized Genomic Epidemiology. One of the most vital and growing public health problems is the emerging and re-emerging of multidrug-resistant (MDR) bacterial infections in the communities and healthcare settings, reinforced by a decline in antimicrobial drug discovery. In recent years, retrospective analysis provided by WGS has had a great impact on the identification and tracking of MDR microorganisms in hospitals and communities. The obtained genomic data are also important for developing novel easy-to-use diagnostic assays for clinics, as well as for antibiotic and therapeutic development at both the personal and population levels. At present, this technology has been successfully applied as an addendum to the real-time diagnostic methods currently used in clinical laboratories. However, the significance of WGS for public health may increase if: (a) unified and user-friendly bioinformatics toolsets for easy data interpretation and management are established, and (b) standards for data validation and verification are developed. Herein, we review the current and future impact of this technology on diagnosis, prevention, treatment, and control of MDR infectious bacteria in clinics and on the global scale.
“…Here, we included 7-dimethylamido 8-azatetracycline (18), which lacks a C9 substitution (Fig. 2 A and G), yet had a similar binding affinity and translation inhibitory activity (both IC 50 s of 0.8 μM) as the 7-methoxy-10-azetidinomethyl pentacycline (IC 50 of 1 μM; Fig.…”
Here we present an X-ray crystallography structure of the clinically relevant tigecycline antibiotic bound to the 70S ribosome. Our structural and biochemical analysis indicate that the enhanced potency of tigecycline results from a stacking interaction with nucleobase C1054 within the decoding site of the ribosome. Singlemolecule fluorescence resonance energy transfer studies reveal that, during decoding, tigecycline inhibits the initial codon recognition step of tRNA accommodation and prevents rescue by the tetracycline-resistance protein TetM.
“…Die AB‐Vorstufe wurde in einer Michael‐Claisen‐Cyclokondensation zur Bildung des C‐Rings umgesetzt,9, 12 und nach hydrogenolytischer Entschützung des A‐Rings [7a] wurden natürliche Tetracycline sowie neue Tetracyclin‐Analoga in hoch konvergenter Weise erhalten. Die Analyse von Myers und Mitarbeitern, dass der C‐Ring des Tetracyclins eine geeignete retrosynthetische Schnittstelle ist, führte zu kurzen Synthesen von 1 ,13 6‐Desoxytetracyclinen (einschließlich 3 ),9 6‐Aryltetracyclinen,12 Pentacyclinen8e, 9, 12 und 8‐Azatetracyclinen,8d um nur einige zu nennen.…”
Section: Methodsunclassified
“…Noch im Jahr 20118d,e, 16, 18 “ dienen Isoxazole dem Zweck der Speicherung des β‐Ketoamidsystems des A‐Rings von Tetracyclinen ”, wie es Stork 1978 vorhersagte 7a. Darüber hinaus erwiesen sich Isoxazole als außerordentlich gut geeignet, um regio‐ und stereoselektive 1,2‐Wanderungen zu dirigieren, indem sie die Bildung eines benachbarten Carbeniumions erleichtern.…”
Reaktion und Gegenreaktion: Tetracycline sind wirksame Antibiotika gegen ein breites Spektrum von Mikroorganismen – eine Schattenseite dieses Erfolgs ist aber die Entwicklung bakterieller Resistenzen, was im Gegenzug die systematische Suche nach neuen Tetracyclin‐Analoga ausgelöst hat. In den letzten Jahren wurden einige Methoden entdeckt, die Zugang zu einer Bandbreite von Tetracyclinderivaten ermöglichen.
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.
