Bolaamphiphile analogues of 12-bis-THA Cl2 are potent antimicrobial therapeutics with distinct mechanisms of action against bacterial, mycobacterial, and fungal pathogens

Di Blasio, Simona, Clarke, Maria, Hind, Charlotte K., Asai, Masanori, Laurence, Louis, Benvenuti, Angelica, Hassan, Mahnoor, Semenya, Dorothy, Man, DeDe Kwun-Wai, Horrocks, Victoria, Manzo, Giorgia, Van Der Lith, Sarah, Lam, Carolyn, Gentile, Eugenio, Annette, Callum, Bosse, Janine, Li, Yanwen, Panaretou, Barry, Langford, Paul R., Robertson, Brian D., Lam, Jenny K. W., Sutton, J. Mark, McArthur, Michael and Mason, A. James (2023) Bolaamphiphile analogues of 12-bis-THA Cl2 are potent antimicrobial therapeutics with distinct mechanisms of action against bacterial, mycobacterial, and fungal pathogens. mSphere, 8 (1). ISSN 2379-5042

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Abstract

12-Bis-THA Cl2 [12,12′-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications.

Item Type:	Article
Additional Information:	Funding information: This work was supported by a BBSRC CASE studentship (BB/L013576/1) for S.D.B. awarded to A.J.M., an NC3Rs Skills & Knowledge Transfer grant (NC/T001240/1), a joint HKU-KCl studentship for D.K.-W.M. awarded to J.K.W.L., Public Health England, and Procarta Biosystems Ltd. and by the King’s Together Multi and Interdisciplinary Research Scheme (Wellcome Trust Institutional Strategic Support Fund; grant reference [204823/Z/16/Z]).
Uncontrolled Keywords:	aminoglycosides,dequalinium chloride,galleria mellonella,synergy,molecular biology,microbiology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	04 Mar 2024 18:38
Last Modified:	06 Mar 2024 09:31
URI:	https://ueaeprints.uea.ac.uk/id/eprint/94549
DOI:	10.1128/msphere.00508-22

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