Metabolic profiling unveils enhanced antibacterial synergy of polymyxin B and teixobactin against multi-drug resistant Acinetobacter baumannii

被引：0

作者：

Hussein, Maytham ^{[1
]}

Kang, Zhisen ^{[1
]}

Neville, Stephanie L. ^{[2
]}

Allobawi, Rafah ^{[1
]}

Thrombare, Varsha ^{[1
]}

Koh, Augustine Jing Jie ^{[1
,3
]}

Wilksch, Jonathan ^{[2
]}

Crawford, Simon ^{[4
]}

Mohammed, Mudher Khudhur ^{[5
]}

McDevitt, Christopher A. ^{[2
]}

Baker, Mark ^{[6
]}

Rao, Gauri G. ^{[7
]}

Li, Jian ^{[4
]}

Velkov, Tony ^{[1
]}

机构：

[1] Monash Univ, Monash Biomed Discovery Inst, Dept Pharmacol, Clayton, Vic 3800, Australia

[2] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, VIC 3010, Australia

[3] Univ Melbourne, Fac Med Dent & Hlth Sci, Sch Biomed Sci, Dept Biochem & Pharmacol, Parkville, Vic 3010, Australia

[4] Monash Univ, Monash Biomed Discovery Inst, Dept Microbiol, Clayton, Vic 3800, Australia

[5] Al Manara Coll Med Sci, Dept Pharm, Maysan, Iraq

[6] Univ Newcastle, Fac Sci & IT, Discipline Biol Sci, Prior Res Ctr Reprod Biol, Univ Dr, Callaghan, NSW 2308, Australia

[7] Univ Southern Calif, Titus Family Dept Clin Pharm, 1985 Zonal Ave, Los Angeles, CA 90089 USA

来源：

SCIENTIFIC REPORTS | 2024年 / 14卷 / 01期

基金：

英国医学研究理事会;

关键词：

Polymyxin B; Teixobactin; <italic>A. baumannii</italic>; Antimicrobial resistance; Metabolomics; STAPHYLOCOCCUS-AUREUS; MECHANISTIC INSIGHTS; GLOBAL METABOLOMICS; IN-VITRO; ANALOGS; BIOSYNTHESIS; ANTIBIOTICS; COMBINATION; PATHWAYS; DESIGN;

D O I：

10.1038/s41598-024-78769-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

This untargeted metabolomics study investigated the synergistic antibacterial activity of polymyxin B and Leu10-teixobactin, a depsipeptide inhibitor of cell wall biosynthesis. Checkerboard microdilution assays revealed a significant synergy against polymyxin-susceptible and -resistant A. baumannii, excluding lipopolysaccharide-deficient variants. Time-kill assays confirmed bactericidal synergy, reducing bacterial burden by approximately 4-6-log10CFU/mL. The combination (2xMIC polymyxin B and 0.5xMIC Leu10-teixobactin) prevented bacterial regrowth after 24 h, indicating sustained efficacy against the emergence of resistant mutants. The analysis of A. baumannii ATCC (TM) 19606 metabolome demonstrated that the polymyxin B-Leu10-teixobactin combination produced more pronounced perturbation compared to the individual antibiotics across all time points (1, 3 and 6 h). Pathway analysis revealed that lipid metabolism, cell envelope biogenesis, and cellular respiration were predominantly impacted by the combination, and to a lesser extent by polymyxin B monotherapy. Leu10-teixobactin treatment alone had only a minor impact on the metabolome, primarily at the 6 h time point. Peptidoglycan assays confirmed the combination's concerted deleterious effects on bacterial cell envelope integrity. Electron microscopy further substantiated these findings, revealing pronounced cell envelope damage, membrane blebbing, and vacuole formation. These findings highlight the potential of the polymyxin B-Leu10-teixobactin combination as an effective treatment in preventing resistance in A. baumannii.

引用

页数：14

共 61 条

[1] Dadgostar P., Antimicrobial resistance: Implications and costs, Infect. Drug Resist, 12, pp. 3903-3910, (2019)
[2] Russo A., Et al., Bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii: Clinical features, therapy and outcome from a multicenter study, J. Infect, 79, 2, pp. 130-138, (2019)
[3] Ventola C.L., The antibiotic resistance crisis: Part 1: Causes and threats, P t, 40, 4, pp. 277-283, (2015)
[4] Hussein M., Et al., Mechanisms underlying synergistic killing of polymyxin B in combination with cannabidiol against Acinetobacter baumannii: A metabolomic study, Pharmaceutics, 14, 4, (2022)
[5] Tacconelli E., Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development, (2017)
[6] Bacterial Pathogens of Public Health Importance to Guide Research, Development and Strategies to Prevent and Control Antimicrobial Resistance, 2024, (2024)
[7] Mulani M.S., Kamble E.E., Kumkar S.N., Tawre M.S., Pardesi K.R., Emerging strategies to combat ESKAPE pathogens in the era of antimicrobial resistance: A review, Front. Microbiol, 10, (2019)
[8] Abadi A., Rizvanov A., Haertle T., Blatt N., World health organization report: Current crisis of antibiotic resistance, BioNanoScience, 9, pp. 778-788, (2019)
[9] Velkov T., Et al., Teaching ‘old’polymyxins new tricks: new-generation lipopeptides targeting gram-negative ‘superbugs’, ACS Chem. Biol, 9, 5, pp. 1172-1177, (2014)
[10] Landman D., Georgescu C., Martin D.A., Quale J., Polymyxins revisited, Clin. Microbiol. Rev, 21, 3, pp. 449-465, (2008)

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