Publications by authors named "Martin Cheramie"

7 Publications

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Author Correction: Extensive genomic diversity among Mycobacterium marinum strains revealed by whole genome sequencing.

Sci Rep 2020 Mar 18;10(1):5246. Epub 2020 Mar 18.

Department of Cell and Molecular Biology, Box 596, Biomedical Centre, SE-751 24, Uppsala, Sweden.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-61218-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078255PMC
March 2020

Ureadepsipeptides as ClpP Activators.

ACS Infect Dis 2019 11 24;5(11):1915-1925. Epub 2019 Oct 24.

Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , 262 Danny Thomas Place , Memphis , Tennessee 38105 , United States.

Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation of the bacterial caseinolytic protease (ClpP). The ability of ClpP activators to kill nongrowing bacteria represents a new opportunity to combat deep-seated biofilm infections. However, the acyldepsipeptide scaffold is subject to rapid metabolism. Herein, we explore alteration of the potentially metabolically reactive α,β unsaturated acyl chain. Through targeted synthesis, a new class of phenyl urea substituted depsipeptide ClpP activators with improved metabolic stability is described. The ureadepsipeptides are potent activators of ClpP and show activity against Gram-positive bacteria, including biofilms. These studies demonstrate that a phenyl urea motif can successfully mimic the double bond, maintaining potency equivalent to acyldepsipeptides but with decreased metabolic liability. Although removal of the double bond from acyldepsipeptides generally has a significant negative impact on potency, structural studies revealed that the phenyl ureadepsipeptides can retain potency through the formation of a third hydrogen bond between the urea and the key Tyr63 residue in the ClpP activation domain. Ureadepsipeptides represent a new class of ClpP activators with improved drug-like properties, potent antibacterial activity, and the tractability to be further optimized.
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http://dx.doi.org/10.1021/acsinfecdis.9b00245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916429PMC
November 2019

Extensive genomic diversity among Mycobacterium marinum strains revealed by whole genome sequencing.

Sci Rep 2018 08 13;8(1):12040. Epub 2018 Aug 13.

Department of Cell and Molecular Biology, Box 596, Biomedical Centre, SE-751 24, Uppsala, Sweden.

Mycobacterium marinum is the causative agent for the tuberculosis-like disease mycobacteriosis in fish and skin lesions in humans. Ubiquitous in its geographical distribution, M. marinum is known to occupy diverse fish as hosts. However, information about its genomic diversity is limited. Here, we provide the genome sequences for 15 M. marinum strains isolated from infected humans and fish. Comparative genomic analysis of these and four available genomes of the M. marinum strains M, E11, MB2 and Europe reveal high genomic diversity among the strains, leading to the conclusion that M. marinum should be divided into two different clusters, the "M"- and the "Aronson"-type. We suggest that these two clusters should be considered to represent two M. marinum subspecies. Our data also show that the M. marinum pan-genome for both groups is open and expanding and we provide data showing high number of mutational hotspots in M. marinum relative to other mycobacteria such as Mycobacterium tuberculosis. This high genomic diversity might be related to the ability of M. marinum to occupy different ecological niches.
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http://dx.doi.org/10.1038/s41598-018-30152-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089878PMC
August 2018

New β-lactam - Tetramic acid hybrids show promising antibacterial activities.

Bioorg Med Chem Lett 2018 10 17;28(18):3105-3112. Epub 2018 Jul 17.

Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

β-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel β-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin - tetramic acid, cephalosporin - tetramic acid, and cephamycin - tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397, and a 7-amino-3-vinyl cephalosporanic acid, 3436, showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25 μg/mL and 3.13 μg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ cephamycin - tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli.
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http://dx.doi.org/10.1016/j.bmcl.2018.07.018DOI Listing
October 2018

Design, synthesis and microbiological evaluation of ampicillin-tetramic acid hybrid antibiotics.

J Antibiot (Tokyo) 2017 Jan 18;70(1):65-72. Epub 2016 May 18.

Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.

Exploiting iron-uptake pathways by conjugating β-lactam antibiotics with iron-chelators, such as catechol and hydroxamic acid is a proven strategy to overcome permeability-related resistance in Gram-negative bacteria. As naturally occurring iron-chelating tetramic acids have not been previously examined for this purpose, an exploratory series of novel ampicillin-tetramic acid hybrids that structurally resemble ureidopenicillins was designed and synthesized. The new analogs were evaluated for the ability to chelate iron and their MIC activities determined against a representative panel of clinically significant bacterial pathogens. The tetramic acid β-lactam hybrids demonstrated a high affinity to iron in the order of 10 M. The hybrids were less active against Gram-positive bacteria. However, against Gram-negative bacteria, their activity was species dependent with several hybrids displaying improved activity over ampicillin against wild-type Pseudomonas aeruginosa. The anti-Gram-negative activities of the hybrids improved in the presence of clavulanic acid revealing that the tetramic acid moiety did not provide added protection against β-lactamases. In addition, the hybrids were found to be efflux pump substrates as their activities markedly improved against pump-inactivated strains. Unlike the catechol and hydroxamic acid siderophore β-lactam conjugates, the activities of the hybrids did not improve under iron-deficient conditions. These results suggest that the tetramic acid hybrids gain permeability via different membrane receptors, or they are outcompeted by native bacterial siderophores with stronger affinities for iron. This study provides a foundation for the further exploitation of the tetramic acid moiety to achieve novel β-lactam anti-Gram-negative agents, providing that efflux and β-lactamase mediated resistance is addressed.
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http://dx.doi.org/10.1038/ja.2016.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116011PMC
January 2017

Comparative Sigma Factor-mRNA Levels in Mycobacterium marinum under Stress Conditions and during Host Infection.

PLoS One 2015 7;10(10):e0139823. Epub 2015 Oct 7.

Department of Cell and Molecular Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.

We have used RNASeq and qRT-PCR to study mRNA levels for all σ-factors in different Mycobacterium marinum strains under various growth and stress conditions. We also studied their levels in M. marinum from infected fish and mosquito larvae. The annotated σ-factors were expressed and transcripts varied in relation to growth and stress conditions. Some were highly abundant such as sigA, sigB, sigC, sigD, sigE and sigH while others were not. The σ-factor mRNA profiles were similar after heat stress, during infection of fish and mosquito larvae. The similarity also applies to some of the known heat shock genes such as the α-crystallin gene. Therefore, it seems probable that the physiological state of M. marinum is similar when exposed to these different conditions. Moreover, the mosquito larvae data suggest that this is the state that the fish encounter when infected, at least with respect to σ-factor mRNA levels. Comparative genomic analysis of σ-factor gene localizations in three M. marinum strains and Mycobacterium tuberculosis H37Rv revealed chromosomal rearrangements that changed the localization of especially sigA, sigB, sigD, sigE, sigF and sigJ after the divergence of these two species. This may explain the variation in species-specific expression upon exposure to different growth conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139823PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596819PMC
June 2016

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

G3 (Bethesda) 2015 Mar 4;5(5):719-40. Epub 2015 Mar 4.

Department of Biology, Albion College, Albion, MI 49224.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.
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http://dx.doi.org/10.1534/g3.114.015966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426361PMC
March 2015
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