The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, ...deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid‐phase strategy to assemble the linear peptide precursor, involving a key on‐resin esterification and an optional on‐resin dimethylation step, before a final solution‐phase macrolactamization between the non‐proteinogenic N‐methyl‐4‐methoxy‐l‐tryptophan amino acid and a bulky N‐methyl‐l‐valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC90’s ranging from 110–360 nm and retained activity against Mtb in Mtb‐infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb, sterilizing cultures after 21 days.
A unified strategy towards antimycobacterial natural products: The total syntheses of the cyclic depsipeptide natural products ohmyungsamycin A, deoxyecumicin, and ecumicin are described. Synthesis was achieved through a unified solid‐phase synthetic strategy and a late‐stage, pre‐organized macrolactamization at an unusually hindered junction. Access to these natural products enabled a detailed comparison on their antimycobacterial activity.
Total Synthesis of Ecumicin Hawkins, Paige M. E; Giltrap, Andrew M; Nagalingam, Gayathri ...
Organic letters,
02/2018, Letnik:
20, Številka:
4
Journal Article
Recenzirano
The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic ...non-proteinogenic amino acids N-methyl-4-methoxy-l-tryptophan and threo-β-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N-methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue. The synthetic natural product possessed potent antimycobacterial activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC90 = 312 nM).
Ohmyungsamycin A and ecumicin are structurally related cyclic depsipeptide natural products that possess activity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). ...Herein, we describe the design and synthesis of a library of analogues of these two natural products using an efficient solid-phase synthesis and late-stage macrolactamization strategy. Lead analogues possessed potent activity against Mtb in vitro (minimum inhibitory concentration 125–500 nM) and were shown to inhibit protein degradation by the mycobacterial ClpC1–ClpP1P2 protease with an associated enhancement of ClpC1 ATPase activity. The most promising analogue from the series exhibited rapid bactericidal killing activity against Mtb, capable of sterilizing cultures after 7 days, and retained bactericidal activity against hypoxic non-replicating Mtb. This natural product analogue was also active in an in vivo zebrafish model of infection.
The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria. To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism ...of the antibiotics cyclomarin A and ecumicin. Quantitative proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3. These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins. To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker. The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic. Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics.
Display omitted
•Cyclomarin A and ecumicin hijack ClpC1P1P2 proteases by mimicking damaged proteins•ClpC2 and ClpC3 function as isolated receptor proteins safeguarding the Clp protease•Homo-BacPROTACs induce degradation of the essential ClpC1 and its ClpC2 security•BacPROTACs present potent antibiotics that efficiently kill M. tuberculosis
Homo-dimeric BacPROTACs induce the self-degradation of essential Clp components of the mycobacterial proteostasis system, introducing a potent antibiotic strategy against M. tuberculosis.
Investments in autism spectrum disorder (ASD) research, guided by the Interagency Autism Coordinating Committee (IACC), have focused disproportionately on etiology over a well-established stakeholder ...priority area: research to improve accessibility and quality of community-based services. This study analyzed National Institutes of Health ASD services research funding from 2008 to 2018 to examine funding patterns, evaluate the impact of IACC objectives, and identify future directions. Approximately 9% of total funds were allocated to services research. This investment remained relatively stable across time and lacked diversity across domains (e.g., area of focus, ages sampled, implementation strategies used). While advancements were observed, including increased prevalence of projects focused on adult samples and on dissemination/implementation and prevention areas, greater investment in service research is critically needed.
Suicidal thoughts and behaviors (STB) and emergency department (ED) utilization are prevalent in autistic youth. The current study surveyed clinicians in a pediatric psychiatric ED to examine ...differences in attitudes on suicide-related care for autistic and non-autistic patient populations. While clinicians rated addressing STB in ASD as important and adaptations to care as necessary, less than half identified ASD as a suicide risk factor and confidence ratings were significantly lower for autistic patients. Previous ASD training predicted confidence and accounted for approximately 25% of the variance in confidence scores. Findings highlight the urgency to develop and disseminate ED clinician training, and address the lack of validated assessment tools, adapted suicide prevention practices, and evidence-based treatments for STB in autistic youth.
The Diviner Lunar Radiometer Experiment on NASA’s Lunar Reconnaissance Orbiter will be the first instrument to systematically map the global thermal state of the Moon and its diurnal and seasonal ...variability. Diviner will measure reflected solar and emitted infrared radiation in nine spectral channels with wavelengths ranging from 0.3 to 400 microns. The resulting measurements will enable characterization of the lunar thermal environment, mapping surface properties such as thermal inertia, rock abundance and silicate mineralogy, and determination of the locations and temperatures of volatile cold traps in the lunar polar regions.
The COVID-19 pandemic, caused by SARS-CoV-2, has led to substantial morbidity, mortality, and disruption globally. Cellular entry of SARS-CoV-2 is mediated by the viral spike protein, and affinity ...ligands to this surface protein have the potential for applications as antivirals and diagnostic reagents. Here, we describe the affinity selection of cyclic peptide ligands to the SARS-CoV-2 spike protein receptor binding domain (RBD) from three distinct libraries (in excess of a trillion molecules each) by mRNA display. We identified six high affinity molecules with dissociation constants (K D) in the nanomolar range (15–550 nM) to the RBD. The highest affinity ligand could be used as an affinity reagent to detect the spike protein in solution by ELISA, and the cocrystal structure of this molecule bound to the RBD demonstrated that it binds to a cryptic binding site, displacing a β-strand near the C-terminus. Our findings provide key mechanistic insight into the binding of peptide ligands to the SARS-CoV-2 spike RBD, and the ligands discovered in this work may find future use as reagents for diagnostic applications.
Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan ...synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against Mtb MurX and potent activity against Mtb in vitro. We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.
ObjectiveRacism is a public health crisis that impacts on children’s mental health, yet mental health service systems are insufficiently focused on addressing racism. Moreover, a focus on ...interpersonal racism and on individual coping with the impacts of racism has been prioritized over addressing structural racism at the level of the service system and associated institutions. In this paper, we examine strategies to address structural racism via policies affecting children’s mental health services.MethodFirst, we identify and analyze federal and state policies focused on racism and mental health equity. Second, we evaluate areas of focus in these policies and discuss the evidence base informing their implementation. Finally, we provide recommendations for what states, counties, cities, and mental health systems can do to promote antiracist evidence-based practices in children’s mental health.ResultsOur analysis highlights gaps and opportunities in the evidence base for policy implementation strategies, including the following: mental health services for youth of color, interventions addressing interpersonal racism and bias in the mental health service system, interventions addressing structural racism, changes to provider licensure and license renewal, and development of the community health workforce.ConclusionRecommendations are provided both within and across systems to catalyze broader systems transformation.
PDF
