DEVELOPMENT OF SMALL MOLECULES AS INHIBITORS OF FTSZ AND RNPA ACTING AS POTENTIAL ANTIMICROBIAL AGENTS
Tesi di Dottorato
Data di Pubblicazione:
2023
Citazione:
DEVELOPMENT OF SMALL MOLECULES AS INHIBITORS OF FTSZ AND RNPA ACTING AS POTENTIAL ANTIMICROBIAL AGENTS / L. Suigo ; coordinatore: G. Aldini ; supervisor: E. Valoti. Dipartimento di Scienze Farmaceutiche, 2023 Jan 13. 35. ciclo, Anno Accademico 2022.
Abstract:
The antimicrobial resistance (AMR) is nowadays one of the most worrying threats of
modern medicine. Recently, AMR has been also called “the silent pandemic” because is as
worrying as the COVID-19 outbreak, but without receiving the same public attention. The
most important organizations such as World Health Organization (WHO) and Centres for
Disease Control and Prevention (CDC) pointed out how the academic work on the
development of new chemical entities as antimicrobials able to interact with new
molecular targets remains one of the key actions to fight antimicrobial resistance (World
Health Organization, 2015).
Within the present work, two innovative bacterial targets have been considered to develop
new potential inhibitors: FtsZ and RnpA.
FtsZ is a 40 kDa protein with 40 -50% of conservation among all bacteria and archaea. This
protein represents the main actor of the bacterial cell division cycle, the essential process
that allows the parent cell to divide through binary fission into two daughter cells. At the
beginning of the cycle, FtsZ polymerizes at the centre of the cell, constituting the “Z-ring”.
This step serves as guide for the continuation of the process, therefore the inhibition of
FtsZ leads to cell filamentation and death. For these reasons, FtsZ arose as a potential target
for the development of new antimicrobials. In the first part of this work, starting from the
insights gained in the last years, new families of benzodioxane-benzamides have been
designed, synthesized, purified and evaluated as potential antimicrobials on S. aureus, B.
subtilis and E. coli. Moreover, FtsZ was validated as the target of these compounds. In
particular, S. aureus and B. subtilis FtsZs were validated as targets through specific cellular
assays, while the capability of these compounds to interact with E. coli FtsZ was
demonstrated through an in vitro study on the isolated protein. Moreover, the cytotoxicity
of all the derivatives was evaluated, and most of the derivatives are characterized by low
to non-detectable cytotoxicity on human cells.
RnpA is a small protein of S. aureus essential for two cellular processes: mRNA degradation
and precursor tRNA (ptRNA) maturation. Indeed, RnpA alone can catalyse the degradation
of bulk mRNA thus promoting mRNA turnover among different growth phases (exponential
and stationary). Furthermore, RnpA is able to associate with a ribozyme to form RNase P,
a riboprotein complex that promotesthe removal of the 5’ leader sequence from precursor tRNA, inducing tRNA maturation. Shortly after the discovery of the essentiality of RnpA, the
investigation of RnpA inhibitors as potential anti-staphylococcal compounds started.
Within the second main body of this work, the structure-activity relationship (SAR) of two
classes of known RnpA inhibitors was evaluated. Modifications of the structures of the two
main RnpA inhibitors, JC2 and RNPA2000, have been designed and applied. The resulting
compounds were tested as antimicrobials on S. aureus, both methicillin-sensitive and
methicillin-resistant. Also in this case, the in vitro profile of inhibition of RnpA as well as the
cytotoxicity of the obtained derivatives were assessed.
With the results obtained in the present work, the understanding of both FtsZ and RnpA
inhibitors was significantly increased, speeding up the development of these important
tools to fight antimicrobial resistance.
Tipologia IRIS:
Tesi di dottorato
Elenco autori:
L. Suigo
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