Article
Biochemistry & Molecular Biology
Gautam Kumar, Asha Kiran Tudu
Summary: Staphylococcus aureus (S. aureus) is a pathogen responsible for various infections with life-threatening complications. The misuse of antibiotics has led to the emergence of multidrug-resistant pathogens. Bacteria have developed mechanisms to avoid the effects of antibiotics. Inhibitors of multidrug efflux pumps are considered alternative therapeutic options. Natural products and their derived compounds can serve as NorA efflux pump inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Applied
Debora Feitosa Muniz, Cristina Rodrigues dos Santos Barbosa, Irwin Rose Alencar de Menezes, Erlanio Oliveira de Sousa, Raimundo Luiz Silva Pereira, Joao Tavares Calixto Junior, Pedro Silvino Pereira, Yedda M. L. S. de Matos, Roger H. S. da Costa, Cicera Datiane de Morais Oliveira-Tintino, Henrique Douglas Melo Coutinho, Jose Maria Barbosa Filho, Gabriela Ribeiro de Sousa, Jaime Ribeiro Filho, Jose Pinto Siqueira-Junior, Saulo Relison Tintino
Summary: This study evaluated the antibacterial activity of eugenol and its derivatives against Staphylococcus aureus NorA efflux pump, showing synergistic effects with some compounds. The findings suggest the potential use of eugenol derivatives in antibacterial drug development, particularly in strains carrying the NorA pump.
Article
Microbiology
Nishtha Chandal, Rushikesh Tambat, Ritu Kalia, Gautam Kumar, Nisha Mahey, Sanjay Jachak, Hemraj Nandanwar
Summary: In this study, a chemically synthesized indole derivative, SMJ-5, was found to be a potent NorA efflux pump inhibitor in Staphylococcus aureus. It increased the accumulation of ethidium bromide and norfloxacin, eradicated biofilm, and prolong the post-antibiotic effect when combined with ciprofloxacin. SMJ-5 also inhibited the staphyloxanthin virulence and showed enhanced bactericidal activity against S. aureus. Additionally, SMJ-5 indirectly inhibited the NorA efflux pump at the transcriptional level.
MICROBIOLOGY SPECTRUM
(2023)
Article
Microbiology
Nishtha Chandal, Rushikesh Tambat, Ritu Kalia, Gautam Kumar, Nisha Mahey, Sanjay Jachak, Hemraj Nandanwar
Summary: In this study, chemically synthesized indole derivatives were screened and a potent NorA efflux pump inhibitor, SMJ-5, was identified. The combination of SMJ-5 and ciprofloxacin showed enhanced bactericidal activity against S. aureus, and could eradicate S. aureus biofilm and prolong the post-antibiotic effect. SMJ-5 also inhibited staphyloxanthin virulence and NorA efflux pump at the transcriptional level indirectly.
MICROBIOLOGY SPECTRUM
(2023)
Article
Chemistry, Medicinal
Martin S. Faillace, Antonio L. Alves Borges Leal, Felipe Araujo de Oliveira Alcantara, Josie H. L. Ferreira, Jose P. de Siqueira-Junior, Carlos E. Sampaio Nogueira, Humberto M. Barreto, Walter J. Pelaez
Summary: Two fluorobenzylidene derivatives showed weak antimicrobial activity against a Staphylococcus aureus strain but significantly enhanced the effectiveness of norfloxacin and ciprofloxacin. The modulation effect of these compounds may involve inhibiting the NorA efflux pump.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Nicholas Cedraro, Rolando Cannalire, Andrea Astolfi, Gianmarco Mangiaterra, Tommaso Felicetti, Salvatore Vaiasicca, Giada Cernicchi, Serena Massari, Giuseppe Manfroni, Oriana Tabarrini, Violetta Cecchetti, Maria Letizia Barreca, Francesca Biavasco, Stefano Sabatini
Summary: The study developed pharmacophore models to identify NorA efflux pump inhibitors, with quinazoline core as the best performing scaffold. The synthesized 2-arylquinazolines demonstrated strong synergism with ciprofloxacin against resistant Staphylococcus aureus strains and low cytotoxicity against human cell lines, showing a promising safety profile.
Article
Chemistry, Medicinal
Tommaso Felicetti, Nicholas Cedraro, Andrea Astolfi, Giada Cernicchi, Gianmarco Mangiaterra, Salvatore Vaiasicca, Serena Massari, Giuseppe Manfroni, Maria Letizia Barreca, Oriana Tabarrini, Francesca Biavasco, Violetta Cecchetti, Carla Vignaroli, Stefano Sabatini
Summary: Antimicrobial resistance (AMR) is a serious global health issue. Efflux pumps play a significant role in the development of resistance and biofilm formation. The search for non-antibiotic molecules that can block efflux pumps is a promising strategy. This study reports a new series of potent derivatives that block efflux pumps and demonstrate synergy with ciprofloxacin against resistant strains of Staphylococcus aureus.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Janaina Esmeraldo Rocha, Thiago Sampaio de Freitas, Jayze da Cunha Xavier, Raimundo Luiz Silva Pereira, Francisco Nascimento Pereira Junior, Carlos Emidio Sampaio Nogueira, Marcia Machado Marinho, Paulo Nogueira Bandeira, Mateus Rodrigues de Oliveira, Emmanuel Silva Marinho, Alexandre Magno Rodrigues Teixeira, Helcio Silva dos Santos, Henrique Douglas Melo Coutinho
Summary: A large number of infections worldwide are caused by multi-resistant bacteria, resulting in approximately 700,000 deaths per year. Chalcones, a class of compounds known for their broad biological activities, including antimicrobial and anticancer properties, are being studied for their potential to combat microbial drug resistance.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Banani Deka, Mrinaly Suri, Sangita Sarma, Anamika Bora, Tejosmita Sen, Anjum Dihingia, Pallab Pahari, Anil Kumar Singh, Moirangthem Veigyabati Devi
Summary: The study synthesized 17 dihydroquinazoline analogues and found that they significantly reduced drug resistance in S. aureus 1199B as NorA efflux pump inhibitors, with low toxicity in human cells, indicating potential as a therapeutic approach.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Infectious Diseases
Elisa Rampacci, Tommaso Felicetti, Giada Cernicchi, Valentina Stefanetti, Stefano Sabatini, Fabrizio Passamonti
Summary: One approach to treating antibiotic-resistant bacteria is to co-administer efflux pump inhibitors (EPIs) with antibiotics to break resistances connected with antibacterial efflux. In this study, ten compounds were evaluated for their ability to inhibit efflux and synergize with different antibiotics in Staphylococcus pseudintermedius. Hit compounds 1, 6, and 8 were considered the best EPIs for S. pseudintermedius. These findings provide valuable data for further optimization and development of EPIs for treating staphylococcal infections.
Article
Biochemistry & Molecular Biology
Fatima Naaz, Arif Khan, Anchala Kumari, Intzar Ali, Faiz Ahmad, Bilal Ahmad Lone, Nazia Ahmad, Inshad Ali Khan, Vikrant Singh Rajput, Abhinav Grover, Syed Shafi
Summary: The NorA efflux pump plays a key role in antibiotic resistance in Staphylococcus aureus. A capsaicin-based compound, 17i, showed significant inhibitory effects on NorA and could potentially serve as a template for drug discovery.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Carolina Ferreira, Patricia Abrantes, Sofia Santos Costa, Miguel Viveiros, Isabel Couto
Summary: This study identified the variability of norA within Staphylococcus aureus and its distribution among other staphylococci. It also demonstrated the applicability of a PCR-based algorithm to detect and differentiate norA alleles, and found the association of norA alleles with specific S. aureus clonal lineages.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Physical
Monica Pica, Nicla Messere, Tommaso Felicetti, Stefano Sabatini, Donatella Pietrella, Morena Nocchetti
Summary: Polymeric composites with bioactive species immobilized on inorganic nanostructured matrix have been studied for reducing bacterial adherence on implanted medical devices. In this study, potent S. aureus NorA efflux pump inhibitors were immobilized on nanometric alpha-zirconium phosphate, resulting in composite films that effectively inhibit biofilm formation by Staphylococcus aureus and Staphylococcus epidermidis. Additionally, the antibacterial activity of ciprofloxacin intercalated in ZrP in combination with ZrP/EPI was evaluated.
Article
Immunology
Jacilene Silva, Janaina Esmeraldo Rocha, Jayze da Cunha Xavier, Thiago Sampaio de Freitas, Henrique Douglas Melo Coutinho, Paulo Nogueira Bandeira, Mateus Rodrigues de Oliveira, Matheus Nunes da Rocha, Emanuelle Machado Marinho, Norberto de Kassio Vieira Monteiro, Lyanna Rodrigues Ribeiro, Ramon Roseo Paula Pessoa Bezerra de Menezes, Marcia Machado Marinho, Alexandre Magno Rodrigues Teixeira, Helcio Silva dos Santos, Emmanuel Silva Marinho
Summary: A large number of infections caused by multi-resistant bacteria result in approximately 700,000 deaths per year worldwide. Chalcones have been studied for their ability to combat microbial resistance to drugs. This research evaluates the antibacterial and antibiotic modifying activity of chalcone (2E)-1-(4'-aminophenyl)-3-(4-methoxyphenyl)-prop-2-en-1-one against Staphylococcus aureus bacteria carrying specific efflux pumps. The results show that chalcone not only has no toxicity on macrophage cells but also synergistically enhances the effects of Norfloxacin and Ethidium Bromide against Staphylococcus aureus. Furthermore, chalcone exhibits favorable physicochemical and pharmacokinetic properties, making it a promising pharmacological active ingredient.
MICROBIAL PATHOGENESIS
(2022)
Article
Microbiology
Nisha Mahey, Rushikesh Tambat, Nishtha Chandal, Dipesh Kumar Verma, Krishan Gopal Thakur, Hemraj Nandanwar
Summary: This study identified six clinically approved drugs that can inhibit the NorA efflux pump, showing synergism with fluoroquinolones and reducing antibiotic resistance in Staphylococcus aureus. These drugs also displayed anti-biofilm properties and efficacy in treating severe S. aureus infections in animal models.
MICROBIOLOGY SPECTRUM
(2021)
Review
Biochemistry & Molecular Biology
Maria Sole Burali, Violetta Cecchetti, Giuseppe Manfroni
Summary: Sulfur and oxygen containing-compounds have gained importance due to their wide range of pharmacological activity, including antiviral properties. Flavivirus infections, such as dengue, West Nile, yellow fever, and Zika viruses, are a growing public health risk. Therefore, the discovery of new anti-flavivirus agents is crucial for providing effective therapies. This review focuses on promising sulfur and oxygen-containing compounds with broad-spectrum activity against different flaviviruses.
CURRENT MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Justyna Godyn, Paula Zareba, Dorota Stary, Maria Kaleta, Kamil J. Kuder, Gniewomir Latacz, Szczepan Mogilski, David Reiner-Link, Annika Frank, Agata Doroz-Plonka, Agnieszka Olejarz-Maciej, Sylwia Sudol-Talaj, Tobias Nolte, Jadwiga Handzlik, Holger Stark, Anna Wieckowska, Barbara Malawska, Katarzyna Kiec-Kononowicz, Dorota Lazewska, Marek Bajda
Summary: The study designed and synthesized a novel series of benzophenone derivatives. Among them, compound 6 showed high affinity for H3R and significant inhibitory activity towards BuChE. In vitro studies demonstrated that compound 6 had moderate metabolic stability and good permeability. In vivo activity tests revealed that compound 6 exhibited analgesic properties in acute and inflammatory pain.
Article
Chemistry, Medicinal
Tommaso Felicetti, Chin Piaw Gwee, Maria Sole Burali, Kitti Wing Ki Chan, Sylvie Alonso, Maria Chiara Pismataro, Stefano Sabatini, Maria Letizia Barreca, Violetta Cecchetti, Subhash G. Vasudevan, Giuseppe Manfroni
Summary: Researchers designed and synthesized a series of sulfonyl anthranilic acid (SAA) derivatives that showed potential inhibition against dengue virus (DENV) infection in cells. These derivatives did not affect the activity of DENV NS5 polymerase. Compounds 26 and 39 exhibited the best inhibitory effects, with EC50 values in the range of 0.54-1.36 μM against cells infected with all four dengue serotypes. The study suggests that SAA derivatives could serve as a valuable starting point for the development of effective antiviral therapeutics for dengue.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Chemistry, Medicinal
Carmine Iorio, Giuseppe Manfroni
FUTURE MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Giulia Marsili, Chiara Acchioni, Anna Lisa Remoli, Donatella Amatore, Rossella Sgarbanti, Marta De Angelis, Roberto Orsatti, Marta Acchioni, Andrea Astolfi, Nunzio Iraci, Simona Puzelli, Marzia Facchini, Edvige Perrotti, Violetta Cecchetti, Stefano Sabatini, Fabiana Superti, Mariangela Agamennone, Maria Letizia Barreca, John Hiscott, Lucia Nencioni, Marco Sgarbanti
Summary: Efficient antiviral compounds are urgently needed to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. In this study, a cell-based screening assay and a small molecule library were used to identify two potential anti-influenza agents that target the NS1 protein and showed activity against A/PR/8/34(H1N1) influenza A virus replication. These compounds also restored IFN-& beta; expression in human lung epithelial cells. This screening approach has the potential to be applied to inhibit other viral targets.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Marta Andres-Mach, Miroslaw Zagaja, Joanna Szala-Rycaj, Aleksandra Szewczyk, Michal Abram, Marcin Jakubiec, Katarzyna Ciepiela, Katarzyna Socala, Piotr Wlaz, Gniewomir Latacz, Nadia Khan, Krzysztof Kaminski
Summary: Epilepsy is a complex neurological disorder with various syndromes and causes. Although antiseizure drugs can provide remission for 70% of patients, there is still a group of about 30% of patients with drug-resistant epilepsy. Therefore, there is a need to develop new and more effective antiseizure drugs. In this study, two analogs, KA-228 and KA-232, were designed and synthesized as structural modifications of the leading compound KA-11. KA-232, a water-soluble salt, showed distinct effectiveness and similar antiseizure protection as KA-11.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Agnieszka Olejarz-Maciej, Szczepan Mogilski, Tadeusz Karcz, Tobias Werner, Katarzyna Kaminska, Jaroslaw Kupczyk, Ewelina Honkisz-Orzechowska, Gniewomir Latacz, Holger Stark, Katarzyna Kiec-Kononowicz, Dorota Lazewska
Summary: Pain is a highly uncomfortable experience that affects daily life. The histamine H-4 receptor (H4R) is a potential target for treating inflammation, immune diseases, and pain. In this study, 19 new compounds with alkyl derivatives of 1,3,5-triazine were obtained, and compound 6 showed promising activity as an H4R ligand. Compound 6 demonstrated anti-inflammatory and analgesic effects in in vivo models, indicating its potential for further investigation.
Article
Infectious Diseases
Elisa Rampacci, Tommaso Felicetti, Giada Cernicchi, Valentina Stefanetti, Stefano Sabatini, Fabrizio Passamonti
Summary: One approach to treating antibiotic-resistant bacteria is to co-administer efflux pump inhibitors (EPIs) with antibiotics to break resistances connected with antibacterial efflux. In this study, ten compounds were evaluated for their ability to inhibit efflux and synergize with different antibiotics in Staphylococcus pseudintermedius. Hit compounds 1, 6, and 8 were considered the best EPIs for S. pseudintermedius. These findings provide valuable data for further optimization and development of EPIs for treating staphylococcal infections.
Article
Biochemistry & Molecular Biology
Michal Zaluski, Dorota Lazewska, Piotr Jasko, Ewelina Honkisz-Orzechowska, Kamil J. Kuder, Andreas Brockmann, Gniewomir Latacz, Malgorzata Zygmunt, Maria Kaleta, Beril Anita Greser, Agnieszka Olejarz-Maciej, Magdalena Jastrzebska-Wiesek, Christin Vielmuth, Christa E. Mueller, Katarzyna Kiec-Kononowicz
Summary: This study synthesized 25 novel xanthine derivatives with potential anti-inflammatory activity and explored their effects on neurodegenerative diseases such as Parkinson's disease. Three compounds were selected for further studies and showed good metabolic stability and anti-inflammatory activity in vitro and in vivo. Further optimization of these compounds and exploration of their therapeutic potential in neurodegenerative diseases are warranted.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Deborah Palazzotti, Tommaso Felicetti, Stefano Sabatini, Stefano Moro, Maria Letizia Barreca, Mattia Sturlese, Andrea Astolfi
Summary: The superbug Staphylococcus aureus (S.aureus) exhibits various resistance mechanisms, such as efflux pumps, which greatly contribute to antimicrobial resistance. The NorA efflux pump activity is particularly associated with S. aureus resistance to fluoroquinolone antibiotics (e.g., ciprofloxacin) by actively extruding them from cells. Efflux pump inhibitors (EPIs) can increase antibiotic concentrations in bacteria and restore their susceptibility, offering a promising strategy against bacterial resistance. The recent release of NorA efflux pump cryo-electron microscopy (cryo-EM) structures in complex with synthetic antigen-binding fragments (Fabs) represents a significant breakthrough in studying S. aureus antibiotic resistance. Combined molecular dynamics and docking experiments were used to investigate the molecular mechanisms behind the interaction between NorA and EPIs, aiming to elucidate how the NorA efflux pump recognizes its inhibitors. The findings provide insights into the dynamic NorA-EPI interactions and lay the foundation for future drug discovery efforts to combat antimicrobial resistance.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Michal Zaluski, Tadeusz Karcz, Anna Drabczynska, Christin Vielmuth, Agnieszka Olejarz-Maciej, Monika Gluch-Lutwin, Barbara Mordyl, Agata Siwek, Grzegorz Satala, Christa E. Muller, Katarzyna Kiec-Kononowicz
Summary: Multitarget drugs designed with a hybrid dopamine-xanthine core have potential as drug candidates for neurodegenerative diseases. Further development of monoamine oxidase B (MAO-B) inhibitors with A(2A) adenosine receptor (A(2A)AR) antagonistic properties led to additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D-2 receptor (D2R) agonistic activity. The compounds showed MAO-B inhibition combined with A(2A)AR affinity, and some compounds exhibited enhanced PDE-inhibitory and D2R-agonistic activity through structural modifications. The multitarget drugs also demonstrated antioxidant properties in vitro and neuroprotective effects in a cellular model.
Article
Chemistry, Medicinal
Sudarshan Murthy, Maria Giulia Nizi, Mirko M. Maksimainen, Serena Massari, Juho Alaviuhkola, Barbara E. Lippok, Chiara Vagaggini, Sven T. Sowa, Albert Galera-Prat, Yashwanth Ashok, Harikanth Venkannagari, Renata Prunskaite-Hyyrylaeinen, Elena Dreassi, Bernhard Luscher, Patricia Korn, Oriana Tabarrini, Lari Lehtio
Summary: We report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold that competes with nicotinamide for binding with human poly- and mono-ADP-ribosylating enzymes. By studying analogues and cocrystal structures, we identified 3-amino derivatives 21 (OUL243) and 27 (OUL232) as potent inhibitors of mono-ADP-ribosyltransferases (mono-ARTs) at nanomolar levels, with 27 being the most potent PARP10 inhibitor ever reported. The TBT scaffold shows potential for future drug development efforts as selective inhibitors against specific enzymes.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
