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Chemistry (Weinheim An Der Bergstrasse,... May 2021The term "privileged structure" refers to a single molecular substructure or scaffold that can serve as a starting point for high-affinity ligands for more than one... (Review)
Review
The term "privileged structure" refers to a single molecular substructure or scaffold that can serve as a starting point for high-affinity ligands for more than one receptor type. In this report, a hitherto overlooked group of privileged substructures is addressed, namely aromatic oligoamides, for which there are natural models in the form of cystobactamids, albicidin, distamycin A, netropsin, and others. The aromatic and heteroaromatic core, together with a flexible selection of substituents, form conformationally well-defined scaffolds capable of specifically binding to conformationally well-defined regions of biomacromolecules such as helices in proteins or DNA often by acting as helices mimics themselves. As such, these aromatic oligoamides have already been employed to inhibit protein-protein and nucleic acid-protein interactions. This article is the first to bring together the scattered knowledge about aromatic oligoamides in connection with biomedical applications.
Topics: DNA; Ligands; Protein Structure, Secondary; Proteins
PubMed: 33481284
DOI: 10.1002/chem.202005086 -
Applied and Environmental Microbiology Nov 2021The production of specialized metabolites by bacteria is usually temporally regulated. This regulation is complex and frequently involves both global and...
The production of specialized metabolites by bacteria is usually temporally regulated. This regulation is complex and frequently involves both global and pathway-specific mechanisms. Streptomyces ambofaciens ATCC23877 produces several specialized metabolites, including spiramycins, stambomycins, kinamycins and congocidine. The production of the first three molecules has been shown to be controlled by one or several cluster-situated transcriptional regulators. However, nothing is known regarding the regulation of congocidine biosynthesis. Congocidine (netropsin) belongs to the family of pyrrolamide metabolites, which also includes distamycin and anthelvencins. Most pyrrolamides bind into the minor groove of DNA, specifically in A/T-rich regions, which gives them numerous biological activities, such as antimicrobial and antitumoral activities. We previously reported the characterization of the pyrrolamide biosynthetic gene clusters of congocidine () in S. ambofaciens ATCC23877, distamycin () in Streptomyces netropsis DSM40846, and anthelvencins () in Streptomyces venezuelae ATCC14583. The three gene clusters contain a gene encoding a putative transcriptional regulator, , , and respectively. Cgc1, Dst1, and Ant1 present a high percentage of amino acid sequence similarity. We demonstrate here that Cgc1, an atypical orphan response regulator, activates the transcription of all genes in the stationary phase of S. ambofaciens growth. We also show that the cluster is constituted of eight main transcriptional units. Finally, we show that congocidine induces the expression of the transcriptional regulator Cgc1 and of the operon containing the resistance genes ( and , coding for an ABC transporter), and propose a model for the transcriptional regulation of the gene cluster. Understanding the mechanisms of regulation of specialized metabolite production can have important implications both at the level of specialized metabolism study (expression of silent gene clusters) and at the biotechnological level (increase of the production of a metabolite of interest). We report here a study on the regulation of the biosynthesis of a metabolite from the pyrrolamide family, congocidine. We show that congocidine biosynthesis and resistance are controlled by Cgc1, a cluster-situated regulator. As the gene clusters directing the biosynthesis of the pyrrolamides distamycin and anthelvencin encode a homolog of Cgc1, our findings may be relevant for the biosynthesis of other pyrrolamides. In addition, our results reveal a new type of feed-forward induction mechanism, in which congocidine induces its own biosynthesis through the induction of the transcription of .
Topics: Distamycins; Gene Expression Regulation, Bacterial; Genes, Bacterial; Multigene Family; Netropsin; Streptomyces
PubMed: 34586912
DOI: 10.1128/AEM.01380-21 -
Antibiotics (Basel, Switzerland) Jul 2022The free-living amoeba is responsible for the central nervous infection granulomatous amoebic encephalitis and sight-threatening infection . Moreover, no effective...
The free-living amoeba is responsible for the central nervous infection granulomatous amoebic encephalitis and sight-threatening infection . Moreover, no effective treatment is currently present, and a combination drug therapy is used. In this study, twelve DNA minor groove binders (MGBs) were synthesized and tested for their antiamoebic activity via amoebicidal, encystation, excystation, and cytopathogenicity assays. It was found that the compounds MGB3, MGB6, MGB22, MGB24, and MGB16 significantly reduce amoeba viability to 76.20%, 59.45%, 66.5%, 39.32%, and 43.21%, respectively, in amoebicidal assays. Moreover, the compounds MGB6, MGB20, MGB22, MGB28, MGB30, MGB32, and MGB16 significantly inhibit cysts, leading to the development of only 46.3%, 39%, 30.3%, 29.6%, 27.8%, 41.5%, and 45.6% cysts. Additionally, the compounds MGB3, MGB4, MGB6, MGB22, MGB24, MGB28, MGB32, and MGB16 significantly reduce the re-emergence of cysts to trophozoites, with viable trophozoites being only 64.3%, 47.3%, 41.4%, 52.9%, 55.4%, 40.6%, 62.1%, and 51.7%. Moreover, the compounds MGB3, MGB4, and MGB6 exhibited the greatest reduction in amoeba-mediated host-cell death, with cell death reduced to 41.5%, 49.4%, and 49.5%. With the following determined, future in vivo studies can be carried out to understand the effect of the compounds on animal models such as mice.
PubMed: 35884189
DOI: 10.3390/antibiotics11070935 -
Molecules (Basel, Switzerland) Aug 2021The recognition of specific DNA sequences in processes such as transcription is associated with a cooperative binding of proteins. Some transcription regulation...
The recognition of specific DNA sequences in processes such as transcription is associated with a cooperative binding of proteins. Some transcription regulation mechanisms involve additional proteins that can influence the binding cooperativity by acting as corepressors or coactivators. In a conditional cooperativity mechanism, the same protein can induce binding cooperativity at one concentration and inhibit it at another. Here, we use calorimetric (ITC) and spectroscopic (UV, CD) experiments to show that such conditional cooperativity can also be achieved by the small DNA-directed oligopeptides distamycin and netropsin. Using a global thermodynamic analysis of the observed binding and (un)folding processes, we calculate the phase diagrams for this system, which show that distamycin binding cooperativity is more pronounced at lower temperatures and can be first induced and then reduced by increasing the netropsin or/and Na+ ion concentration. A molecular interpretation of this phenomenon is suggested.
Topics: DNA; Distamycins; Netropsin; Oligopeptides; Protein Binding; Sodium; Thermodynamics; Transcription, Genetic
PubMed: 34500619
DOI: 10.3390/molecules26175188 -
ACS Chemical Biology Apr 2020Anthelvencins A and B are pyrrolamide metabolites produced by ATCC 14583 and 14585. Isolated in 1965, they were reported to exhibit anthelmintic and moderate...
Anthelvencins A and B are pyrrolamide metabolites produced by ATCC 14583 and 14585. Isolated in 1965, they were reported to exhibit anthelmintic and moderate antibacterial activities. In this study, we revise the structure of anthelvencin A and identify a third anthelvencin metabolite, bearing two -methylated pyrrole groups, which we named anthelvencin C. We sequenced the genome of ATCC 14583 and identified a gene cluster predicted to direct the biosynthesis of anthelvencins. Functional analysis of this gene cluster confirmed its involvement in anthelvencin biosynthesis and allowed us to propose a biosynthetic pathway for anthelvencins. In addition to a nonribosomal peptide synthetase (NRPS), the assembly of anthelvencins involves an enzyme from the ATP-grasp ligase family, Ant23. We propose that Ant23 uses a PCP-loaded 4-aminopyrrole-2-carboxylate as substrate. As observed for the biosynthesis of the other pyrrolamides congocidine (produced by ATCC 25877) and distamycin (produced by DSM 40846), the NRPS assembling anthelvencins is composed of stand-alone domains only. Such NRPSs, sometimes called type II NRPSs, are less studied than the classical multimodular NRPSs. Yet, they constitute an interesting model to study protein-protein interactions in NRPSs and are good candidates for combinatorial biosynthesis approaches.
Topics: Bacterial Proteins; Multigene Family; Peptide Synthases; Protein Domains; Pyrroles; Streptomyces
PubMed: 32129986
DOI: 10.1021/acschembio.9b00960 -
In Silico Pharmacology 2021Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV) and the novel SARS-CoV-2 evade the host innate...
UNLABELLED
Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV) and the novel SARS-CoV-2 evade the host innate immunity, and subsequently the adaptive immune response, employing one protease called Papain-like protease (PLpro). The PLpro and the 3CL main protease are responsible for the cleavage of the polyproteins encoded by the + sense RNA genome of the virus to produce several non-structured proteins (NSPs). However, the PLpro also performs deubiquitination and deISGylation of host proteins and signaling molecules, and thus antagonize the host innate immune response, since ubiquitination and ISGylation are critical processes which invoke host's antiviral immune responses. Thus, to maintain host antiviral defense, inhibition of the PLpro is the primary therapeutic strategy. Furthermore, inhibition of the enzyme prevents replication of the virus. The present study employs molecular modeling approaches to determine potential of different approved and repurposed drugs and other compounds as inhibitors of the SARS-CoV-2 PLpro. The results of the study demonstrated that drugs like Stallimycin, and known protease inhibitors including Telaprevir, Grazoprevir and Boceprevir, were highly potent in inhibiting the enzyme. In addition, several plant-derived polyphenols, including Corylifol A and Kazinol J, were found to be potent inhibitors. Based on the findings, we suggest that clinical trials be initiated with these inhibitors. So far, PLpro inhibition has been given less attention as a strategy to contain COVID-19 pandemic, and thus the present study is of high significance and has therapeutic implications in containing the pandemic.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40203-021-00085-y.
PubMed: 33842190
DOI: 10.1007/s40203-021-00085-y -
Acta Biochimica Et Biophysica Sinica Jan 2020Distamycin (DST) is a well-characterized DNA minor groove binder with antivirus activity and antitumor potency. Two separate gene clusters (a 28-kb cluster and a 7-kb...
Distamycin (DST) is a well-characterized DNA minor groove binder with antivirus activity and antitumor potency. Two separate gene clusters (a 28-kb cluster and a 7-kb cluster) have recently been identified to coordinately encode the biosynthetic machinery of DST in Streptomyces netropsis. Here we report a gene cassette, which is linked to the aforementioned smaller dst gene cluster and plays an important role in the self-resistance to DST in S. netropsis. This cassette consists of three uncharacterized genes that might be implicated in DNA replication/repair. Knockout of the cassette led to the decrease in the production of DST, while heterologous expression of part of the cassette in S. lividans made it become resistant to both DST and mitomycin C, another DNA-binding agent. More interestingly, homologs of these three genes were found in genomes of other actinomyces that produce DNA-binding antibiotics, suggesting that a novel common mechanism in addition to pumping may enable these strains to resist the cytotoxic metabolites they produced.
Topics: Anti-Bacterial Agents; Cells, Cultured; DNA Repair; DNA Replication; DNA-Binding Proteins; Distamycins; Drug Resistance, Bacterial; Escherichia coli; Gene Knockout Techniques; Genes, Bacterial; Mitomycin; Multigene Family; Streptomyces; Streptomyces lividans
PubMed: 31833535
DOI: 10.1093/abbs/gmz133