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3 Biotech

, 9:122 | Cite as

Understanding lipidomic basis of iron limitation induced chemosensitization of drug-resistant Mycobacterium tuberculosis

  • Rahul Pal
  • Saif HameedEmail author
  • Parveen Kumar
  • Sarman Singh
  • Zeeshan FatimaEmail author
Original Article

Abstract

Under limited micronutrients condition, Mycobacterium tuberculosis (MTB) has to struggle for acquisition of the limited micronutrients available in the host. One such crucial micronutrient that MTB requires for the growth and sustenance is iron. The present study aimed to sequester the iron supply of MTB to control drug resistance in MTB. We found that iron restriction renders hypersensitivity to multidrug-resistant MTB strains against first-line anti-TB drugs. To decipher the effect of iron restriction on possible mechanisms of chemosensitization and altered cellular circuitry governing drug resistance and virulence of MTB, we explored MTB cellular architecture. We could identify non-intact cell envelope, tampered MTB morphology and diminished mycolic acid under iron restricted MDR-MTB cells. Deeper exploration unraveled altered lipidome profile observed through conventional TLC and advanced mass spectrometry-based LC–ESI–MS techniques. Lipidome analysis not only depicted profound alterations of various lipid classes which are crucial for pathogenecity but also exposed leads such as indispensability of iron to sustain metabolic, genotoxic and oxidative stresses. Furthermore, iron deprivation led to inhibited biofilm formation and capacity of MTB to adhere buccal epithelial cells. Lastly, we demonstrated enhanced survival of Mycobacterium-infected Caenorhabditis elegans model under iron limitation. The present study offers evidence and proposes alteration of lipidome profile and affected virulence traits upon iron chelation. Taken together, iron deprivation could be a potential strategy to rescue MDR and enhance the effectiveness of existing anti-TB drugs.

Keywords

Myocbacterium Iron Lipids Membrane Lipidomics Glyoxylate cycle Biofilm 

Abbreviations

MTB

Mycobacterium tuberculosis

MDR

Multidrug resistance

ADC

Albumin dextrose catalase

OADC

Oleic albumin dextrose catalase

2,4 DNP

2,4 dinitrophenol

CFW

Calcoflour white

CV

Crystal violet

INT

Iodonitrotetrazolium chloride

SEM

Scanning electron microscopy

PI

Propidium iodide

DCFDA

2′,7′-dichlorofluorescin diacetate

DAPI

4′,6-diamidino-2-phenylindole

MS

Malate synthase

ICLI

Isocitrate lyase

ROS

Reactive oxygen species

EMB

Ethambutol

RIF

Rifampicin

INH

Isoniazid

STP

Streptomycin

2,2,-BP

2,2, Bipyridyl

FA

Fatty acid

GL

Glycerolipid

GPL

Glycerophospholipid

PK

Polykedide

PR

Prenol

SCL

Saccharolipide

Notes

Acknowledgements

Z. F. thanks Board of Research in Nuclear Sciences (BRNS), Mumbai (2013/37B/45/BRNS/1903) for the financial assistance. We thank Anindya Ghosh for providing wild-type C. elegans (N2) and Escherichia coli OP50 strains as generous gift. We are grateful to Mandira Varma-Basil, Pramod Mehta and Yossef Av-Gay for providing MTB MDR strains, M. marinium and ΔPknG mutant as generous gifts, respectively. We thank Sanjeev Kanojiya for assisting us in mass spectrometry experiments. We thank Varatharajan Sabareesh for his intellectual support in lipidome data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

13205_2019_1645_MOESM1_ESM.doc (928 kb)
Supplementary material 1 (DOC 927 KB)
13205_2019_1645_MOESM2_ESM.xls (148 kb)
Supplementary material 2 Excel sheet showing the data obtained from MS-LAMP in untreated cells (XLS 147 KB)
13205_2019_1645_MOESM3_ESM.xls (180 kb)
Supplementary material 3 Excel sheet showing the data obtained from MS-LAMP in 2, 2,-BP treated cells (XLS 179 KB)

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Copyright information

© King Abdulaziz City for Science and Technology 2019

Authors and Affiliations

  1. 1.Amity Institute of BiotechnologyAmity University HaryanaGurugramIndia
  2. 2.Division of Clinical Microbiology and Molecular Medicine, Department of Laboratory MedicineAll India Institute of Medical SciencesNew DelhiIndia

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