Mohamad S sabbah - Academia.edu (original) (raw)

Papers by Mohamad S sabbah

Research paper thumbnail of Fragment-Based Design of Mycobacterium Tuberculosis InhA Inhibitors

Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. Inh... more Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. InhA, the target of the first line pro-drug isoniazid, an enoyl ACP-reductase, has been the focus of numerous drug discovery efforts attempting to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, we describe the screening and validation cascade of a fragment library and employ a fragment growing strategy using structure-guided fragment-based design to develop potent InhA inhibitors.

Research paper thumbnail of The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase

Tuberculosis (Edinburgh, Scotland), Sep 1, 2018

The search for compounds with biological activity for many diseases is turning increasingly to dr... more The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of C-uracil and C-leucine similar to the effect of rifampicin, a known inhibitor of M. tuberculosis RNA polymerase. Surprisingly, the co-administration of pyronaridine (2.5 μg/ml) and rifampicin resulted in in vitro synergy with an MIC 0.0019-0.0009 μg/mL. This was mirrored in a THP-1 macrophage infection model, with a 16-fold MIC reduction for rifampicin when the two compounds were co-administered versus rifampicin alone. Docking pyronaridine in M. tuberculosis RNA polymerase suggested the potential for it to bind outside of the RNA polymerase rifampicin binding pocket. Pyronaridine was also found to...

Research paper thumbnail of Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis

Journal of medicinal chemistry, Jan 12, 2018

Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are neede... more Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible ( Mth) IMPDH ΔCBS inhibitors identified a low affinity phenylimidazole derivative. X-ray crystallography of the Mth IMPDH ΔCBS-IMP-inhibitor complex revealed that two molecules of the fragment were bound in the NAD binding pocket of IMPDH. Linking the two molecules of the fragment afforded compounds with more than 1000-fold improvement in IMPDH affinity over the initial fragment hit.

Research paper thumbnail of Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach

Frontiers in Pharmacology, 2017

Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberc... more Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC 50 below 50 µM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.

Research paper thumbnail of Appropriateness of Empirical Antimicrobial Therapy for Patients Admitted from the Emergency Department with Severe Sepsis or Septic Shock and Blood Stream Infection

Research paper thumbnail of N,N’-alkylated Imidazolium-Derivatives Act as Quorum-Sensing Inhibitors Targeting the Pectobacterium atrosepticum-Induced Symptoms on Potato Tubers

International Journal of Molecular Sciences, 2013

Bacteria belonging to the Pectobacterium genus are the causative agents of the blackleg and soft-... more Bacteria belonging to the Pectobacterium genus are the causative agents of the blackleg and soft-rot diseases that affect potato plants and tubers worldwide. In Pectobacterium, the expression of the virulence genes is controlled by quorum-sensing (QS) and N-acylhomoserine lactones (AHLs). In this work, we screened a chemical library of QS-inhibitors (QSIs) and AHL-analogs to find novel QSIs targeting the virulence of Pectobacterium. Four N,N'-bisalkylated imidazolium salts were identified as QSIs; they were active at the µM range. In potato tuber assays, two of them were able to decrease the

Research paper thumbnail of Risk of Clostridium difficile infection in intensive care unit patients with sepsis exposed to metronidazole

Infectious Diseases, 2015

Antimicrobial agents used to treat Clostridium difficile infection (CDI), such as metronidazole a... more Antimicrobial agents used to treat Clostridium difficile infection (CDI), such as metronidazole and vancomycin, have been used during antibiotic treatment of other infections to try to prevent the development of CDI. We evaluated the hypothesis that intensive care unit (ICU) patients who receive metronidazole as part of an antibiotic treatment regimen for sepsis have a lower risk of subsequently developing CDI. This was a nested case-control study in a cohort of ICU patients who received antibiotic therapy for sepsis. A total of 10 012 patients aged ≥ 18 years were admitted to the Cooper University Hospital medical/surgical ICU from 1/1/2003 to 12/31/2008. After applying inclusion criteria including having received antibiotic therapy for sepsis and subsequently having developed CDI, 67 cases were identified. The cases were matched for age, gender, date of ICU admission, and hospital length of stay to 67 controls that also received antibiotic therapy for sepsis but did not subsequently develop CDI. In the multivariate analysis, there was no association between metronidazole exposure and the risk of CDI (odds ratio (OR) = 0.57; p = 0.23). The only significant associations on multivariate analysis were antifungal therapy (OR = 0.30; p = 0.02) and aminoglycoside and/or colistin therapy (OR = 0.17; p = 0.02). No association was found between metronidazole use and subsequent CDI in ICU patients who received antibiotic therapy for sepsis.

Research paper thumbnail of Characterization of the Quorum Sensing Regulon in <i>Acidithiobacillus ferrooxidans</i>

Advanced Materials Research, 2013

Bioleaching is the solubilization of metals from ores by microorganisms. This process is more eff... more Bioleaching is the solubilization of metals from ores by microorganisms. This process is more efficient than conventional methods in the metal recovery from low grade ores while decreasing the operating cost and the environmental impact. Among the bioleaching bacteria, the Gram-negative chemolithoautotrophic acidophilic Acidithiobacillus ferrooxidans has the ability to adhere to mineral surface and to form biofilm. The genes involved in the production of this biofilm are controlled by a cellular communication system called Quorum Sensing (QS). The QS occurs mainly through the production of acyl homoserine lactones (AHLs). A functional QS system has been identified in At. ferrooxidans with an acyl synthase (AfeI) and a transcriptional regulator (AfeR). Here, our purpose is to characterize the quorum sensing regulon and particularly the genes involved in biofilm formation in At. ferrooxidans. This has been done by cell adhesion experiments comparing At. ferrooxidans grown with or with...

Research paper thumbnail of A new route towards fimbrolide analogues: importance of the exomethylene motif in LuxR dependent quorum sensing inhibition

Research paper thumbnail of AHL-dependent quorum sensing inhibition: Synthesis and biological evaluation of α-(N-alkyl-carboxamide)-γ-butyrolactones and α-(N-alkyl-sulfonamide)-γ-butyrolactones

Bioorganic & Medicinal Chemistry Letters, 2011

New N-acylhomoserine lactone (AHL) analogues in which the amide function is replaced by a reverse... more New N-acylhomoserine lactone (AHL) analogues in which the amide function is replaced by a reverse-amide one have been studied as AHL QS modulators. The series of compounds consists of α-(N-alkyl-carboxamide)-γ-butyrolactones, α-(N-alkyl-sulfonamide)-γ-butyrolactones, and 2-(N-alkyl-carboxamide)-cyclopentanones and cyclopentanols. Most active compounds exhibited antagonist activities against LuxR reaching the 30 μM range.

Research paper thumbnail of LuxR-dependent quorum sensing: Computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones

Bioorganic & Medicinal Chemistry Letters, 2010

Research paper thumbnail of Synthesis and biological evaluation of new N-acyl-homoserine-lactone analogues, based on triazole and tetrazole scaffolds, acting as LuxR-dependent quorum sensing modulators

Bioorganic & Medicinal Chemistry, 2012

New analogues of N-acyl-homoserine-lactone (AHL), in which the amide was replaced by a triazole o... more New analogues of N-acyl-homoserine-lactone (AHL), in which the amide was replaced by a triazole or tetrazole ring, were prepared and tested for their activity as LuxR-dependent QS modulators. Several compounds showed a level of antagonistic or agonistic activity, notably some 1,4-triazolic and 1,5-tetrazolic derivatives, whereas the 2,5-tetrazolic compounds were inactive. In 1,5-tetrazoles, substituted with butyrolactone and an alkyl chain, the activity was reversed, depending on the connection between the lactone and the tetrazole. The C-N connected compounds were agonists whereas the C-C connected ones were antagonists.

Research paper thumbnail of LuxR dependent quorum sensing inhibition by N,N′-disubstituted imidazolium salts

Bioorganic & Medicinal Chemistry, 2011

Thirty N,N 0-disubstituted imidazolium salts have been synthesized and evaluated as LuxR antagoni... more Thirty N,N 0-disubstituted imidazolium salts have been synthesized and evaluated as LuxR antagonists. Substitution on one of the imidazolium nitrogen atoms includes benzhydryl, fluorenyl or cyclopentyl substituent, and alkyl chains of various lengths on the second one. Most of these compounds displayed antagonist activity, with IC 50 reaching the micromolar range for the most active ones. The disubstituted imidazolium scaffold is thus shown to be a new pertinent pharmacophore in the field of AHL dependent QS inhibition.

Research paper thumbnail of ChemInform Abstract: Organocatalyzed Decarboxylative Protonation Process from Meldrum′s Acid: Enantioselective Synthesis of Isoxazolidinones

ChemInform, 2014

Organocatalyzed Decarboxylative Protonation Process from Meldrum's Acid: Enantioselective Synthes... more Organocatalyzed Decarboxylative Protonation Process from Meldrum's Acid: Enantioselective Synthesis of Isoxazolidinones.-The presented procedure gives a broad range of isoxazolidin-5-ones with good enantioselectivities and high yields, with exception of compound (V), from readily available Meldrum's acid derivatives. The obtained products can be effectively converted into the corresponding β-amino acids [e.g.

Research paper thumbnail of Developments in Meyers’ Lactamization Methodology: En Route to Bi(hetero)aryl Structures with Defined Axial Chirality

The Journal of Organic Chemistry, 2013

Research paper thumbnail of Organocatalysed decarboxylative protonation process from Meldrum's acid: enantioselective synthesis of isoxazolidinones

Chemical Communications, 2013

Research paper thumbnail of Fragment-Based Design of Mycobacterium Tuberculosis InhA Inhibitors

Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. Inh... more Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. InhA, the target of the first line pro-drug isoniazid, an enoyl ACP-reductase, has been the focus of numerous drug discovery efforts attempting to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, we describe the screening and validation cascade of a fragment library and employ a fragment growing strategy using structure-guided fragment-based design to develop potent InhA inhibitors.

Research paper thumbnail of The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase

Tuberculosis (Edinburgh, Scotland), Sep 1, 2018

The search for compounds with biological activity for many diseases is turning increasingly to dr... more The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of C-uracil and C-leucine similar to the effect of rifampicin, a known inhibitor of M. tuberculosis RNA polymerase. Surprisingly, the co-administration of pyronaridine (2.5 μg/ml) and rifampicin resulted in in vitro synergy with an MIC 0.0019-0.0009 μg/mL. This was mirrored in a THP-1 macrophage infection model, with a 16-fold MIC reduction for rifampicin when the two compounds were co-administered versus rifampicin alone. Docking pyronaridine in M. tuberculosis RNA polymerase suggested the potential for it to bind outside of the RNA polymerase rifampicin binding pocket. Pyronaridine was also found to...

Research paper thumbnail of Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis

Journal of medicinal chemistry, Jan 12, 2018

Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are neede... more Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible ( Mth) IMPDH ΔCBS inhibitors identified a low affinity phenylimidazole derivative. X-ray crystallography of the Mth IMPDH ΔCBS-IMP-inhibitor complex revealed that two molecules of the fragment were bound in the NAD binding pocket of IMPDH. Linking the two molecules of the fragment afforded compounds with more than 1000-fold improvement in IMPDH affinity over the initial fragment hit.

Research paper thumbnail of Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach

Frontiers in Pharmacology, 2017

Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberc... more Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC 50 below 50 µM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.

Research paper thumbnail of Appropriateness of Empirical Antimicrobial Therapy for Patients Admitted from the Emergency Department with Severe Sepsis or Septic Shock and Blood Stream Infection

Research paper thumbnail of N,N’-alkylated Imidazolium-Derivatives Act as Quorum-Sensing Inhibitors Targeting the Pectobacterium atrosepticum-Induced Symptoms on Potato Tubers

International Journal of Molecular Sciences, 2013

Bacteria belonging to the Pectobacterium genus are the causative agents of the blackleg and soft-... more Bacteria belonging to the Pectobacterium genus are the causative agents of the blackleg and soft-rot diseases that affect potato plants and tubers worldwide. In Pectobacterium, the expression of the virulence genes is controlled by quorum-sensing (QS) and N-acylhomoserine lactones (AHLs). In this work, we screened a chemical library of QS-inhibitors (QSIs) and AHL-analogs to find novel QSIs targeting the virulence of Pectobacterium. Four N,N'-bisalkylated imidazolium salts were identified as QSIs; they were active at the µM range. In potato tuber assays, two of them were able to decrease the

Research paper thumbnail of Risk of Clostridium difficile infection in intensive care unit patients with sepsis exposed to metronidazole

Infectious Diseases, 2015

Antimicrobial agents used to treat Clostridium difficile infection (CDI), such as metronidazole a... more Antimicrobial agents used to treat Clostridium difficile infection (CDI), such as metronidazole and vancomycin, have been used during antibiotic treatment of other infections to try to prevent the development of CDI. We evaluated the hypothesis that intensive care unit (ICU) patients who receive metronidazole as part of an antibiotic treatment regimen for sepsis have a lower risk of subsequently developing CDI. This was a nested case-control study in a cohort of ICU patients who received antibiotic therapy for sepsis. A total of 10 012 patients aged ≥ 18 years were admitted to the Cooper University Hospital medical/surgical ICU from 1/1/2003 to 12/31/2008. After applying inclusion criteria including having received antibiotic therapy for sepsis and subsequently having developed CDI, 67 cases were identified. The cases were matched for age, gender, date of ICU admission, and hospital length of stay to 67 controls that also received antibiotic therapy for sepsis but did not subsequently develop CDI. In the multivariate analysis, there was no association between metronidazole exposure and the risk of CDI (odds ratio (OR) = 0.57; p = 0.23). The only significant associations on multivariate analysis were antifungal therapy (OR = 0.30; p = 0.02) and aminoglycoside and/or colistin therapy (OR = 0.17; p = 0.02). No association was found between metronidazole use and subsequent CDI in ICU patients who received antibiotic therapy for sepsis.

Research paper thumbnail of Characterization of the Quorum Sensing Regulon in <i>Acidithiobacillus ferrooxidans</i>

Advanced Materials Research, 2013

Bioleaching is the solubilization of metals from ores by microorganisms. This process is more eff... more Bioleaching is the solubilization of metals from ores by microorganisms. This process is more efficient than conventional methods in the metal recovery from low grade ores while decreasing the operating cost and the environmental impact. Among the bioleaching bacteria, the Gram-negative chemolithoautotrophic acidophilic Acidithiobacillus ferrooxidans has the ability to adhere to mineral surface and to form biofilm. The genes involved in the production of this biofilm are controlled by a cellular communication system called Quorum Sensing (QS). The QS occurs mainly through the production of acyl homoserine lactones (AHLs). A functional QS system has been identified in At. ferrooxidans with an acyl synthase (AfeI) and a transcriptional regulator (AfeR). Here, our purpose is to characterize the quorum sensing regulon and particularly the genes involved in biofilm formation in At. ferrooxidans. This has been done by cell adhesion experiments comparing At. ferrooxidans grown with or with...

Research paper thumbnail of A new route towards fimbrolide analogues: importance of the exomethylene motif in LuxR dependent quorum sensing inhibition

Research paper thumbnail of AHL-dependent quorum sensing inhibition: Synthesis and biological evaluation of α-(N-alkyl-carboxamide)-γ-butyrolactones and α-(N-alkyl-sulfonamide)-γ-butyrolactones

Bioorganic & Medicinal Chemistry Letters, 2011

New N-acylhomoserine lactone (AHL) analogues in which the amide function is replaced by a reverse... more New N-acylhomoserine lactone (AHL) analogues in which the amide function is replaced by a reverse-amide one have been studied as AHL QS modulators. The series of compounds consists of α-(N-alkyl-carboxamide)-γ-butyrolactones, α-(N-alkyl-sulfonamide)-γ-butyrolactones, and 2-(N-alkyl-carboxamide)-cyclopentanones and cyclopentanols. Most active compounds exhibited antagonist activities against LuxR reaching the 30 μM range.

Research paper thumbnail of LuxR-dependent quorum sensing: Computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones

Bioorganic & Medicinal Chemistry Letters, 2010

Research paper thumbnail of Synthesis and biological evaluation of new N-acyl-homoserine-lactone analogues, based on triazole and tetrazole scaffolds, acting as LuxR-dependent quorum sensing modulators

Bioorganic & Medicinal Chemistry, 2012

New analogues of N-acyl-homoserine-lactone (AHL), in which the amide was replaced by a triazole o... more New analogues of N-acyl-homoserine-lactone (AHL), in which the amide was replaced by a triazole or tetrazole ring, were prepared and tested for their activity as LuxR-dependent QS modulators. Several compounds showed a level of antagonistic or agonistic activity, notably some 1,4-triazolic and 1,5-tetrazolic derivatives, whereas the 2,5-tetrazolic compounds were inactive. In 1,5-tetrazoles, substituted with butyrolactone and an alkyl chain, the activity was reversed, depending on the connection between the lactone and the tetrazole. The C-N connected compounds were agonists whereas the C-C connected ones were antagonists.

Research paper thumbnail of LuxR dependent quorum sensing inhibition by N,N′-disubstituted imidazolium salts

Bioorganic & Medicinal Chemistry, 2011

Thirty N,N 0-disubstituted imidazolium salts have been synthesized and evaluated as LuxR antagoni... more Thirty N,N 0-disubstituted imidazolium salts have been synthesized and evaluated as LuxR antagonists. Substitution on one of the imidazolium nitrogen atoms includes benzhydryl, fluorenyl or cyclopentyl substituent, and alkyl chains of various lengths on the second one. Most of these compounds displayed antagonist activity, with IC 50 reaching the micromolar range for the most active ones. The disubstituted imidazolium scaffold is thus shown to be a new pertinent pharmacophore in the field of AHL dependent QS inhibition.

Research paper thumbnail of ChemInform Abstract: Organocatalyzed Decarboxylative Protonation Process from Meldrum′s Acid: Enantioselective Synthesis of Isoxazolidinones

ChemInform, 2014

Organocatalyzed Decarboxylative Protonation Process from Meldrum's Acid: Enantioselective Synthes... more Organocatalyzed Decarboxylative Protonation Process from Meldrum's Acid: Enantioselective Synthesis of Isoxazolidinones.-The presented procedure gives a broad range of isoxazolidin-5-ones with good enantioselectivities and high yields, with exception of compound (V), from readily available Meldrum's acid derivatives. The obtained products can be effectively converted into the corresponding β-amino acids [e.g.

Research paper thumbnail of Developments in Meyers’ Lactamization Methodology: En Route to Bi(hetero)aryl Structures with Defined Axial Chirality

The Journal of Organic Chemistry, 2013

Research paper thumbnail of Organocatalysed decarboxylative protonation process from Meldrum's acid: enantioselective synthesis of isoxazolidinones

Chemical Communications, 2013