The rapid rise of multi-resistant bacteria is a global health threat. This is especially serious for Gram-negative bacteria in which the impermeable outer membrane (OM) acts as a shield against antibiotics. The develop-ment of new drugs with novel modes of actions to combat multi-drug resistant pathogens requires the selection of suitable processes to be targeted. The LPS export pathway is an excellent under exploited target for drug development. Indeed, LPS is the major determinant of the OM permeability barrier, and its biogenetic pathway is conserved in most Gram-negatives. Here we describe efforts to identify inhibitors of the multiprotein Lpt system that transports LPS to the cell surface. Despite none of these molecules has been approved for clinical use, they may represent valuable compounds for optimization. Finally, the recent discovery of a link between inhibition of LPS biogenesis and changes in peptidoglycan structure uncovers additional targets to develop novel therapeutic strategies.

Targeting the LPS export pathway for the development of novel therapeutics / P. Sperandeo, A.M. Martorana, M. Zaccaria, A. Polissi. - In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH. - ISSN 1879-2596. - 1870:2(2023 Feb), pp. 119406.1-119406.11. [10.1016/j.bbamcr.2022.119406]

Targeting the LPS export pathway for the development of novel therapeutics

P. Sperandeo
Primo
;
A.M. Martorana
Secondo
;
M. Zaccaria
Penultimo
;
A. Polissi
Ultimo
2023

Abstract

The rapid rise of multi-resistant bacteria is a global health threat. This is especially serious for Gram-negative bacteria in which the impermeable outer membrane (OM) acts as a shield against antibiotics. The develop-ment of new drugs with novel modes of actions to combat multi-drug resistant pathogens requires the selection of suitable processes to be targeted. The LPS export pathway is an excellent under exploited target for drug development. Indeed, LPS is the major determinant of the OM permeability barrier, and its biogenetic pathway is conserved in most Gram-negatives. Here we describe efforts to identify inhibitors of the multiprotein Lpt system that transports LPS to the cell surface. Despite none of these molecules has been approved for clinical use, they may represent valuable compounds for optimization. Finally, the recent discovery of a link between inhibition of LPS biogenesis and changes in peptidoglycan structure uncovers additional targets to develop novel therapeutic strategies.
Antimicrobial discovery; Cell envelope homeostasis; LPS; LPS biogenesis inhibitors; Lpt complex
Settore BIO/19 - Microbiologia Generale
   Escaping the ESKAPEs: integrated pipelines for new antibacterial drugs
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   20208LLXEJ_004

   Piano di Sostegno alla Ricerca 2015-2017 - Linea 2 "Dotazione annuale per attività istituzionali" (anno 2021)
   UNIVERSITA' DEGLI STUDI DI MILANO
feb-2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/969222
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