Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs

Z. Dvorak, M. Klapholz, TP. Burris, BP. Willing, A. Gioiello, R. Pellicciari, F. Galli, J. March, SJ. O'Keefe, RB. Sartor, CH. Kim, M. Levy, S. Mani,

. 2020 ; 98 (4) : 343-349. [pub] 20200806

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.

Persistent link   https://www.medvik.cz/link/bmc20027786

Grant support
R01 ES030197 NIEHS NIH HHS - United States
R01 CA222469 NCI NIH HHS - United States

For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls-hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc20027786
003      
CZ-PrNML
005      
20210114152347.0
007      
ta
008      
210105s2020 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1124/molpharm.120.000035 $2 doi
035    __
$a (PubMed)32764096
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Dvorak, Zdenek $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
245    10
$a Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs / $c Z. Dvorak, M. Klapholz, TP. Burris, BP. Willing, A. Gioiello, R. Pellicciari, F. Galli, J. March, SJ. O'Keefe, RB. Sartor, CH. Kim, M. Levy, S. Mani,
520    9_
$a For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls-hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.
650    _2
$a Bacteria $x chemie $7 D001419
650    _2
$a biologické přípravky $x chemie $7 D001688
650    _2
$a objevování léků $7 D055808
650    _2
$a lidé $7 D006801
650    _2
$a indoly $x chemie $x farmakologie $7 D007211
650    _2
$a ligandy $7 D008024
650    _2
$a molekulární mimikry $7 D018716
655    _2
$a časopisecké články $7 D016428
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
655    _2
$a práce podpořená grantem $7 D013485
655    _2
$a Research Support, U.S. Gov't, Non-P.H.S. $7 D013486
700    1_
$a Klapholz, Max $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a Burris, Thomas P $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a Willing, Benjamin P $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a Gioiello, Antimo $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a Pellicciari, Roberto $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a Galli, Francesco $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a March, John $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a O'Keefe, Stephen J $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a Sartor, R Balfour $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.) ryan_balfour_sartor@med.unc.edu.
700    1_
$a Kim, Chang H $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).
700    1_
$a Levy, Maayan $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.) maayanle@pennmedicine.upenn.edu.
700    1_
$a Mani, Sridhar $u Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic (Z.D.); Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania (M.K., M.L.); The Center for Clinical Pharmacology, Washington University in St. Louis and St. Louis College of Pharmacy, St. Louis, Missouri (T.P.B.); Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta (B.P.W.); Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy (A.G., F.G.); TES Pharma, Corso Vannucci, Perugia, Italy (R.P.); The Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York (J.M.); Division of Gastroenterology and Nutrition, UPMC Presbyterian Hospital, Pittsburgh, Pennsylvania (S.J.O.); Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (R.B.S.); Department of Pathology, Mary H. Weiser Food Allergy Center, and Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan (C.H.K.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.) sridhar.mani@einsteinmed.org.
773    0_
$w MED00003399 $t Molecular pharmacology $x 1521-0111 $g Roč. 98, č. 4 (2020), s. 343-349
856    41
$u https://pubmed.ncbi.nlm.nih.gov/32764096 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20210105 $b ABA008
991    __
$a 20210114152345 $b ABA008
999    __
$a ok $b bmc $g 1608121 $s 1118966
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2020 $b 98 $c 4 $d 343-349 $e 20200806 $i 1521-0111 $m Molecular pharmacology $n Mol Pharmacol $x MED00003399
GRA    __
$a R01 ES030197 $p NIEHS NIH HHS $2 United States
GRA    __
$a R01 CA222469 $p NCI NIH HHS $2 United States
LZP    __
$a Pubmed-20210105

Find record

Citation metrics

Archiving options