ANTIBIO-BAC: exploring the bacterial cell wall as a target for novel antibiotherapies

• Grant number: 17/12436-9
• Support Opportunities: Research Projects - SPEC Program
• Duration: February 01, 2018 - January 31, 2023
• Field of knowledge: Biological Sciences - Mathematics - Chemistry of Macromolecules
• Principal Investigator: Andrea Dessen de Souza e Silva
• Grantee: Andrea Dessen de Souza e Silva
• Visiting researcher institution: Institut de Biologie Structurale (IBS), France
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil
• Associated researchers: Andre Oliveira de Souza Lima ; Daniel Maragno Trindade ; Daniela Barretto Barbosa Trivella ; Roberto Gomes de Souza Berlinck
• Associated scholarship(s): 21/01309-1 - Isolation and characterization of secondary metabolites with potential for antibacterial action, BP.PD; 19/27148-4 - Structural characterization of complexes involved in bacterial cell wall elongation, BP.PD; 19/13497-7 - Discovery of antimicrobial molecules related to bacterial cell wall formation, BP.PD; 18/04344-0 - Structural characterization of type II secretion system (T2SS) effectors of Acinetobacter baumannii, BP.DD; 15/19906-5 - Identification of new antibacterial agents in libraries of natural products, BP.DR

Abstract

Bacterial resistance to antibiotics is a pressing, worldwide problem, and the 'drug development void' of the last several years has permitted that major human pathogens become resistant to all antibiotics, including 'last resort molecules'. This reality demands a multi-disciplinary effort towards the exploration of new ideas that could lead to the development of treatments that explore yet untapped sources and target key bacterial processes that are essential for bacterial survival. At the LNBio, one of my group's recent interests has been the screening for new, potential antibiotics in libraries of natural products prepared from the Brazilian biodiversity, a vast, totally novel, yet untapped source of antimicrobials. An initial screening campaign performed at the LNBio identified >30 original samples that block the action of Penicillin-Binding Proteins (PBPs), key bacterial cell wall biosynthesis enzymes, as well as growth of both Gram-negative and Gram-positive bacteria. In addition, thanks to support from FAPESP, we structurally characterized the first complex between a PBP and a partner molecule that assures bacterial cell wall elongation, which represents an initial glimpse into new interfaces that can be targeted with small molecules viewing novel antibiotic development. The present grant application views the expansion of these very exciting results through the characterization of higher order cell wall biosynthesis complexes as well as the continuation of the effort of identification of new natural product inhibitors of antibiotic-resistance systems. This is a high risk, high gain project that combines state-of-the-art structural biology with microbiology and biophysics, and will impact both biology and public health. ANTIBIO-BAC thus consolidates efforts to study different aspects of bacterial cell wall biogenesis and drug resistance in order to understand molecular interactions that play key roles in bacterial survival and virulence, and identify unique molecules that can lead to novel antibiotherapies. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MIYACHIRO, MAYARA M.; GRANATO, DANIELA; TRINDADE, DANIEL MARAGNO; EBEL, CHRISTINE; PAES LEME, ADRIANA FRANCO; DESSEN, ANDREA. Complex Formation between Mur Enzymes from Streptococcus pneumoniae. BIOCHEMISTRY, v. 58, n. 30, p. 3314-3324, JUL 30 2019. (17/12436-9, 11/52067-6, 13/02451-0)

LADDOMADA, FEDERICA; MIYACHIRO, MAYARA M.; JESSOP, MATTHEW; PATIN, DELPHINE; JOB, VIVIANA; MENGIN-LECREULX, DOMINIQUE; LE ROY, ALINE; EBEL, CHRISTINE; BREYTON, CECILE; GUTSCHE, IRINA; et al. The MurG glycosyltransferase provides an oligomeric scaffold for the cytoplasmic steps of peptidoglycan biosynthesis in the human pathogen Bordetella pertussis. SCIENTIFIC REPORTS, v. 9, MAR 15 2019. (11/52067-6, 13/02451-0, 17/12436-9)

DE FELICIO, RAFAEL; BALLONE, PATRICIA; BAZZANO, CRISTINA FREITAS; ALVES, LUIZ F. G.; SIGRIST, RENATA; INFANTE, GINA POLO; NIERO, HENRIQUE; RODRIGUES-COSTA, FERNANDA; FERNANDES, ARTHUR ZANETTI NUNES; TONON, LUCIANE A. C.; et al. Chemical Elicitors Induce Rare Bioactive Secondary Metabolites in Deep-Sea Bacteria under Laboratory Conditions. METABOLITES, v. 11, n. 2, FEB 2021. (14/10753-9, 17/12436-9, 15/19906-5)

DE OLIVEIRA SILVA, YURI RAFAEL; CONTRERAS-MARTEL, CARLOS; MACHEBOEUF, PAULINE; DESSEN, ANDREA. Bacterial secretins: Mechanisms of assembly and membrane targeting. Protein Science, v. 29, n. 4, FEB 2020. (17/12436-9, 18/04344-0)

BERTRAND, QUENTIN; JOB, VIVIANA; MAILLARD, ANTOINE P.; IMBERT, LIONEL; TEULON, JEAN-MARIE; FAVIER, ADRIEN; PELLEQUER, JEAN-LUC; HUBER, PHILIPPE; ATTREE, INA; DESSEN, ANDREA. Exolysin (ExlA) from Pseudomonas aeruginosa Punctures Holes into Target Membranes Using a Molten Globule Domain. Journal of Molecular Biology, v. 432, n. 16, p. 4466-4480, JUL 24 2020. (17/12436-9)

MARTINS, ALEXANDRE; CONTRERAS-MARTEL, CARLOS; JANET-MAITRE, MANON; MIYACHIRO, MAYARA M.; ESTROZI, LEANDRO F.; TRINDADE, DANIEL MARAGNO; MALOSPIRITO, CAIQUE C.; RODRIGUES-COSTA, FERNANDA; IMBERT, LIONEL; JOB, VIVIANA; et al. Self-association of MreC as a regulatory signal in bacterial cell wall elongation. NATURE COMMUNICATIONS, v. 12, n. 1, MAY 20 2021. (17/12436-9, 15/19906-5, 11/52067-6, 18/07148-7)

RODRIGUES-COSTA, FERNANDA; SLIVINSKI, JULIANO; IOCA, LAURA P.; BERTONHA, ARIANE F.; DE FELICIO, RAFAEL; DA CUNHA, MARCOS GUILHERME; DA MATA MADEIRA, PAULO VINICIUS; CAUZ, ANA C. G.; TRINDADE, DANIEL MARAGNO; FREIRE, VITOR F.; et al. Merulinic acid C overcomes gentamicin resistance in Enterococcus faecium. BIOORGANIC CHEMISTRY, v. 100, JUL 2020. (16/05133-7, 13/50228-8, 11/52067-6, 17/12436-9, 15/19906-5, 14/11980-9)

ZOUHIR, SAMIRA; CONTRERAS-MARTEL, CARLOS; MARAGNO TRINDADE, DANIEL; ATTREE, INA; DESSEN, ANDREA; MACHEBOEUF, PAULINE. MagC is a NplC/P60-like member of the alpha-2-macroglobulin Mag complex of Pseudomonas aeruginosa that interacts with peptidoglycan. FEBS Letters, JUN 2021. (11/52067-6, 13/01962-0, 17/12436-9)

ZOUHIR, SAMIRA; CONTRERAS-MARTEL, CARLOS; MARAGNO TRINDADE, DANIEL; ATTREE, INA; DESSEN, ANDREA; MACHEBOEUF, PAULINE. MagC is a NplC/P60-like member of the alpha-2-macroglobulin Mag complex of Pseudomonas aeruginosa that interacts with peptidoglycan. FEBS Letters, v. 595, n. 15, p. 2034-2046, AUG 2021. (13/01962-0, 17/12436-9, 11/52067-6)