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Mechanisms of a Mycobacterium tuberculosis Active Peptide

Rao, Komal Umashankar LU ; Li, Ping LU ; Welinder, Charlotte LU ; Tenland, Erik LU ; Gourdon, Pontus LU ; Sturegård, Erik LU ; Ho, James C.S. and Godaly, Gabriela LU orcid (2023) In Pharmaceutics 15(2).
Abstract

Multidrug-resistant tuberculosis (MDR) continues to pose a threat to public health. Previously, we identified a cationic host defense peptide with activity against Mycobacterium tuberculosis in vivo and with a bactericidal effect against MDR M. tuberculosis at therapeutic concentrations. To understand the mechanisms of this peptide, we investigated its interactions with live M. tuberculosis and liposomes as a model. Peptide interactions with M. tuberculosis inner membranes induced tube-shaped membranous structures and massive vesicle formation, thus leading to bubbling cell death and ghost cell formation. Liposomal studies revealed that peptide insertion into inner membranes induced changes in the peptides’ secondary structure and that... (More)

Multidrug-resistant tuberculosis (MDR) continues to pose a threat to public health. Previously, we identified a cationic host defense peptide with activity against Mycobacterium tuberculosis in vivo and with a bactericidal effect against MDR M. tuberculosis at therapeutic concentrations. To understand the mechanisms of this peptide, we investigated its interactions with live M. tuberculosis and liposomes as a model. Peptide interactions with M. tuberculosis inner membranes induced tube-shaped membranous structures and massive vesicle formation, thus leading to bubbling cell death and ghost cell formation. Liposomal studies revealed that peptide insertion into inner membranes induced changes in the peptides’ secondary structure and that the membranes were pulled such that they aggregated without permeabilization, suggesting that the peptide has a strong inner membrane affinity. Finally, the peptide targeted essential proteins in M. tuberculosis, such as 60 kDa chaperonins and elongation factor Tu, that are involved in mycolic acid synthesis and protein folding, which had an impact on bacterial proliferation. The observed multifaceted targeting provides additional support for the therapeutic potential of this peptide.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
antimicrobial peptides, mechanisms of action, Mycobacterium tuberculosis, treatment
in
Pharmaceutics
volume
15
issue
2
article number
540
publisher
MDPI AG
external identifiers
  • scopus:85149137531
  • pmid:36839864
ISSN
1999-4923
DOI
10.3390/pharmaceutics15020540
language
English
LU publication?
yes
id
4937e25a-d9c2-4d5a-b5b7-2c38079a499e
date added to LUP
2023-03-20 11:32:18
date last changed
2024-06-14 00:37:33
@article{4937e25a-d9c2-4d5a-b5b7-2c38079a499e,
  abstract     = {{<p>Multidrug-resistant tuberculosis (MDR) continues to pose a threat to public health. Previously, we identified a cationic host defense peptide with activity against Mycobacterium tuberculosis in vivo and with a bactericidal effect against MDR M. tuberculosis at therapeutic concentrations. To understand the mechanisms of this peptide, we investigated its interactions with live M. tuberculosis and liposomes as a model. Peptide interactions with M. tuberculosis inner membranes induced tube-shaped membranous structures and massive vesicle formation, thus leading to bubbling cell death and ghost cell formation. Liposomal studies revealed that peptide insertion into inner membranes induced changes in the peptides’ secondary structure and that the membranes were pulled such that they aggregated without permeabilization, suggesting that the peptide has a strong inner membrane affinity. Finally, the peptide targeted essential proteins in M. tuberculosis, such as 60 kDa chaperonins and elongation factor Tu, that are involved in mycolic acid synthesis and protein folding, which had an impact on bacterial proliferation. The observed multifaceted targeting provides additional support for the therapeutic potential of this peptide.</p>}},
  author       = {{Rao, Komal Umashankar and Li, Ping and Welinder, Charlotte and Tenland, Erik and Gourdon, Pontus and Sturegård, Erik and Ho, James C.S. and Godaly, Gabriela}},
  issn         = {{1999-4923}},
  keywords     = {{antimicrobial peptides; mechanisms of action; Mycobacterium tuberculosis; treatment}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{MDPI AG}},
  series       = {{Pharmaceutics}},
  title        = {{Mechanisms of a Mycobacterium tuberculosis Active Peptide}},
  url          = {{http://dx.doi.org/10.3390/pharmaceutics15020540}},
  doi          = {{10.3390/pharmaceutics15020540}},
  volume       = {{15}},
  year         = {{2023}},
}