Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages

Dj, Greenwood; Santos, Mariana Silva dos; Huang, Song; Russell, Mark; Collinson, Lucy; MacRae, James I.; West, Andrew; Jiang, Haibo; Gutierrez, Maximiliano G.

doi:10.1126/science.aat9689

Cited by 126 publications

(148 citation statements)

References 33 publications

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“…LC-MS begins with the extraction of lipids from plasma. The most popular method is liquid-liquid extraction using a mixture of dichloromethane/methanol or butanol/methanol [7][8][9]. Methanol destroys and precipitates lipoproteins, and dichloromethane guarantees the effective extraction of a wide range of lipid species from the precipitated lipoproteins.…”

Section: Liquid Chromatography (Lc)-based Techniquesmentioning

confidence: 99%

A Review of Lipidomics of Cardiovascular Disease Highlights the Importance of Isolating Lipoproteins

Ding

Rexrode

2020

Metabolites

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Cutting-edge lipidomic profiling measures hundreds or even thousands of lipids in plasma and is increasingly used to investigate mechanisms of cardiovascular disease (CVD). In this review, we introduce lipidomic techniques, describe distributions of lipids across lipoproteins, and summarize findings on the association of lipids with CVD based on lipidomics. The main findings of 16 cohort studies were that, independent of total and high-density lipoprotein cholesterol (HDL-c), ceramides (d18:1/16:0, d18:1/18:0, and d18:1/24:1) and phosphatidylcholines (PCs) containing saturated and monounsaturated fatty acyl chains are positively associated with risks of CVD outcomes, while PCs containing polyunsaturated fatty acyl chains (PUFA) are inversely associated with risks of CVD outcomes. Lysophosphatidylcholines (LPCs) may be positively associated with risks of CVD outcomes. Interestingly, the distributions of the identified lipids vary across lipoproteins: LPCs are primarily contained in HDLs, ceramides are mainly contained in low-density lipoproteins (LDLs), and PCs are distributed in both HDLs and LDLs. Thus, the potential mechanism behind previous findings may be related to the effect of the identified lipids on the biological functions of HDLs and LDLs. Only eight studies on the lipidomics of HDL and non-HDL particles and CVD outcomes have been conducted, which showed that higher triglycerides (TAGs), lower PUFA, lower phospholipids, and lower sphingomyelin content in HDLs might be associated with a higher risk of coronary heart disease (CHD). However, the generalizability of these studies is a major concern, given that they used case-control or cross-sectional designs in hospital settings, included a very small number of participants, and did not correct for multiple testing or adjust for blood lipids such as HDL-c, low-density lipoprotein cholesterol (LDL-c), or TAGs. Overall, findings from the literature highlight the importance of research on lipidomics of lipoproteins to enhance our understanding of the mechanism of the association between the identified lipids and the risk of CVD and allow the identification of novel lipid biomarkers in HDLs and LDLs, independent of HDL-c and LDL-c. Lipidomic techniques show the feasibility of this exciting research direction, and the lack of high-quality epidemiological studies warrants well-designed prospective cohort studies.

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Section: Liquid Chromatography (Lc)-based Techniquesmentioning

confidence: 99%

A Review of Lipidomics of Cardiovascular Disease Highlights the Importance of Isolating Lipoproteins

Ding

Rexrode

2020

Metabolites

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“…These phospholipids may thus be involved in the increase of autophagy and mycobacterial phagosome-lysosome fusion upon BDQ treatment. Consistent with this hypothesis, recent work has shown that BDQ accumulates in host cell lipid droplets and is transferred to MTB as the droplets are consumed by the bacteria, enhancing MTB killing (Greenwood et al, 2019).…”

Section: Discussionmentioning

confidence: 79%

The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

Giraud-Gatineau

Coya

Maure

et al. 2019

Preprint

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AbstractAntibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed macrophages into potent bactericidal phagocytes. We found that 1,495 genes were differentially expressed in M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of genes involved in metabolism, lysosome biogenesis and activation. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including nitric oxide production, phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB (TFEB), involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.

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“…Interestingly, it has been proposed that targeting host lipid droplets in foamy macrophages may enhance efficacy of anti-TB agents. The lipophilic antibiotics stored in lipid droplets would be transferred to the intracellular pathogen as M. tuberculosis consumes host lipid droplets as a carbon source for growth [16].…”

Section: Preferable Characteristics Of Targets and Enzyme Inhibitors/mentioning

confidence: 99%

Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

et al. 2020

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Roughly a third of the world’s population is estimated to have latent Mycobacterium tuberculosis infection, being at risk of developing active tuberculosis (TB) during their lifetime. Given the inefficacy of prophylactic measures and the increase of drug-resistant M. tuberculosis strains, there is a clear and urgent need for the development of new and more efficient chemotherapeutic agents, with selective toxicity, to be implemented on patient treatment. The component enzymes of the shikimate pathway, which is essential in mycobacteria and absent in humans, stand as attractive and potential targets for the development of new drugs to treat TB. This review gives an update on published work on the enzymes of the shikimate pathway and some insight on what can be potentially explored towards selective drug development.

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Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages

Cited by 126 publications

References 33 publications

A Review of Lipidomics of Cardiovascular Disease Highlights the Importance of Isolating Lipoproteins

A Review of Lipidomics of Cardiovascular Disease Highlights the Importance of Isolating Lipoproteins

The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

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