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Targeting the bacterial cytoskeleton of the Burkholderia cepacia complex for antimicrobial development: A cautionary tale

Lookup NU author(s): Dr Sonya Carnell, Dr John Perry, Dr Lee Borthwick, Dr Daniela Vollmer, Dr Jacob Biboy, Professor Waldemar Vollmer, Dr Anjam Khan, Professor Anthony De Soyza

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Burkholderia cepacia complex (BCC) bacteria are a group of opportunistic pathogens that cause severe lung infections in cystic fibrosis (CF). Treatment of BCC infections is difficult, due to the inherent and acquired multidrug resistance of BCC. There is a pressing need to find new bacterial targets for antimicrobials. Here, we demonstrate that the novel compound Q22, which is related to the bacterial cytoskeleton destabilising compound A22, can reduce the growth rate and inhibit growth of BCC bacteria. We further analysed the phenotypic effects of Q22 treatment on BCC virulence traits, to assess its feasibility as an antimicrobial. BCC bacteria were grown in the presence of Q22 with a broad phenotypic analysis, including resistance to H2O2-induced oxidative stress, changes in the inflammatory potential of cell surface components, and in-vivo drug toxicity studies. The influence of the Q22 treatment on inflammatory potential was measured by monitoring the cytokine responses of BCC whole cell lysates, purified lipopolysaccharide, and purified peptidoglycan extracted from bacterial cultures grown in the presence or absence of Q22 in differentiated THP-1 cells. BCC bacteria grown in the presence of Q22 displayed varying levels of resistance to H2 O2-induced oxidative stress, with some strains showing increased resistance after treatment. There was strain-to-strain variation in the pro-inflammatory ability of bacterial lysates to elicit TNFα and IL-1β from human myeloid cells. Despite minimal toxicity previously shown in vitro with primary CF cell lines, in-vivo studies demonstrated Q22 toxicity in both zebrafish and mouse infection models. In summary, destabilisation of the bacterial cytoskeleton in BCC, using compounds such as Q22, led to increased virulence-related traits in vitro. These changes appear to vary depending on strain and BCC species. Future development of antimicrobials targeting the BCC bacterial cytoskeleton may be hampered if such effects translate into the in-vivo environment of the CF infection.


Publication metadata

Author(s): Carnell SC, Perry JD, Borthwick L, Vollmer D, Biboy J, Facchini M, Bragonzi A, Silipo A, Vergunst AC, Vollmer W, Khan ACM, De Soyza A

Publication type: Article

Publication status: Published

Journal: International Journal of Molecular Sciences

Year: 2018

Volume: 19

Issue: 6

Online publication date: 30/05/2018

Acceptance date: 17/05/2018

Date deposited: 11/06/2018

ISSN (print): 1661-6596

ISSN (electronic): 1422-0067

Publisher: MDPI AG

URL: https://doi.org/10.3390/ijms19061604

DOI: 10.3390/ijms19061604


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