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A new antibiotic with potent activity targets MscL.

Iscla I, Wray R, Blount P, Larkins-Ford J, Conery AL, Ausubel FM, Ramu S, Kavanagh A, Huang JX, Blaskovich MA, Cooper MA, Obregon-Henao A, Orme I, Tjandra ES, Stroeher UH, Brown MH, Macardle C, van Holst N, Ling Tong C, Slattery AD, Gibson CT, Raston CL, Boulos RA - J. Antibiot. (2015)

Bottom Line: As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL.Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans.Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, UT Southwestern Med Ctr, Dallas, TX, USA.

ABSTRACT
The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

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(a) Diagrammatic representation of target amino acids Leu19, Ala20 and Val23 in close proximity to the E. coli MscL channel gate, which were used for the de novo design of the designated ligands. (b) Docking energies (kcal mol−1) of the ligands. (c) Iterative in silico docking of lead ligand 2, which gave rise to new class of antimicrobials including compounds 8–12. A full color version of this figure is available at The Journal of Antibiotics journal online.
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fig1: (a) Diagrammatic representation of target amino acids Leu19, Ala20 and Val23 in close proximity to the E. coli MscL channel gate, which were used for the de novo design of the designated ligands. (b) Docking energies (kcal mol−1) of the ligands. (c) Iterative in silico docking of lead ligand 2, which gave rise to new class of antimicrobials including compounds 8–12. A full color version of this figure is available at The Journal of Antibiotics journal online.

Mentions: To explore the potential of MscL as a target for antibiotics, we developed a spatial map between the exposed oxygen atoms of amino acids, lining the gate of the MscL channel. This three-dimensional spatial map was used for the de novo design14 of several potential ligands capable of hydrogen bonding to the MscL channel amino acids as shown in Figure 1a. We calculated that one of these potential ligands, 1,2,4-tris[2′-(4″-phenol)ethyl]benzene (ligand 2), had the lowest docking energy (Figure 1b). We then further optimized the binding of ligand 2 using iterative in silico docking models to identify related structures with lower docking energies (Figure 1c). Specifically, the hydroxyl groups in ligand 2 were substituted with a variety of functional groups (aldehydes, amide cations, amino, carboxyl, chloride). With reference to Figure 1c, we found that the addition of carboxyl groups to the ‘b', ‘c' and ‘d' positions resulted in the most favorable docking energies. This ligand, 8, was determined to have a free energy of binding equivalent to ~−55.94 kJ mol−1, which is higher than previously screened candidates from the National Cancer Institute database. Thus, compound 8 and its analogs represent a potentially novel class of antimicrobials based on p-carboethoxy-tristyryl and p-carboethoxy-terastyrenyl benzene derivatives.


A new antibiotic with potent activity targets MscL.

Iscla I, Wray R, Blount P, Larkins-Ford J, Conery AL, Ausubel FM, Ramu S, Kavanagh A, Huang JX, Blaskovich MA, Cooper MA, Obregon-Henao A, Orme I, Tjandra ES, Stroeher UH, Brown MH, Macardle C, van Holst N, Ling Tong C, Slattery AD, Gibson CT, Raston CL, Boulos RA - J. Antibiot. (2015)

(a) Diagrammatic representation of target amino acids Leu19, Ala20 and Val23 in close proximity to the E. coli MscL channel gate, which were used for the de novo design of the designated ligands. (b) Docking energies (kcal mol−1) of the ligands. (c) Iterative in silico docking of lead ligand 2, which gave rise to new class of antimicrobials including compounds 8–12. A full color version of this figure is available at The Journal of Antibiotics journal online.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430313&req=5

fig1: (a) Diagrammatic representation of target amino acids Leu19, Ala20 and Val23 in close proximity to the E. coli MscL channel gate, which were used for the de novo design of the designated ligands. (b) Docking energies (kcal mol−1) of the ligands. (c) Iterative in silico docking of lead ligand 2, which gave rise to new class of antimicrobials including compounds 8–12. A full color version of this figure is available at The Journal of Antibiotics journal online.
Mentions: To explore the potential of MscL as a target for antibiotics, we developed a spatial map between the exposed oxygen atoms of amino acids, lining the gate of the MscL channel. This three-dimensional spatial map was used for the de novo design14 of several potential ligands capable of hydrogen bonding to the MscL channel amino acids as shown in Figure 1a. We calculated that one of these potential ligands, 1,2,4-tris[2′-(4″-phenol)ethyl]benzene (ligand 2), had the lowest docking energy (Figure 1b). We then further optimized the binding of ligand 2 using iterative in silico docking models to identify related structures with lower docking energies (Figure 1c). Specifically, the hydroxyl groups in ligand 2 were substituted with a variety of functional groups (aldehydes, amide cations, amino, carboxyl, chloride). With reference to Figure 1c, we found that the addition of carboxyl groups to the ‘b', ‘c' and ‘d' positions resulted in the most favorable docking energies. This ligand, 8, was determined to have a free energy of binding equivalent to ~−55.94 kJ mol−1, which is higher than previously screened candidates from the National Cancer Institute database. Thus, compound 8 and its analogs represent a potentially novel class of antimicrobials based on p-carboethoxy-tristyryl and p-carboethoxy-terastyrenyl benzene derivatives.

Bottom Line: As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL.Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans.Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, UT Southwestern Med Ctr, Dallas, TX, USA.

ABSTRACT
The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

Show MeSH
Related in: MedlinePlus