Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling

Betts, Joanna C.; Lukey, Pauline T.; Robb, Linda C.; McAdam, Ruth A.; Duncan, Ken

doi:10.1046/j.1365-2958.2002.02779.x

Cited by 1,395Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyInfectious Diseases and Tuberculosis

Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling

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Betts, Joanna C., Lukey, Pauline T., Robb, Linda C., McAdam, Ruth A., Duncan, Ken·2002·Molecular Microbiology

DOI 10.1046/j.1365-2958.2002.02779.x

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Abstract

Summary: The search for new TB drugs that rapidly and effectively sterilize the tissues and are thus able to shorten the duration of chemotherapy from the current 6 months has been hampered by a lack of understanding of the metabolism of the bacterium when in a ‘persistent’ or latent form. Little is known about the condition in which the bacilli survive, although laboratory models have shown that Mycobacterium tuberculosis can exist in a non‐growing, drug‐resistant state that may mimic persistence in vivo. Using nutrient starvation, we have established a model in which M. tuberculosis arrests growth, decreases its respiration rate and is resistant to isoniazid, rifampicin and metronidazole. We have used microarray and proteome analysis to investigate the response of M. tuberculosis to nutrient starvation. Proteome analysis of 6‐week‐starved cultures revealed the induction of several proteins. Microarray analysis enabled us to monitor gene expression during adaptation to nutrient starvation and confirmed the changes seen at the protein level. This has provided evidence for slowdown of the transcription apparatus, energy metabolism, lipid biosynthesis and cell division in addition to induction of the stringent response and several other genes that may play a role in maintaining long‐term survival within the host. Thus, we have generated a model with which we can search for agents active against persistent M. tuberculosis and revealed a number of potential targets expressed under these conditions.

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During carbon starvation and slow growth, mycobacteria switch to alternative electron donors.
“During carbon starvation and slow growth, mycobacteria switch to alternative electron donors (16, 20, 45) (Figure 2).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [20]
The Energy metabolism section (page not specified in our copy) reports downregulation of the primary aerobic respiratory chain during nutrient starvation and suggests that other enzymes may help recycle NAD+ or contribute to metabolism. It does not establish that mycobacteria switch to alternative electron donors during carbon starvation and slow growth; the tested condition was nutrient starvation in PBS. (LLM, conf=0.79)
Experimental — accuracy not yet measured
PknA and PknB phosphorylate EmbR, activating transcription of embC, embA and embB during growth, thus ensuring that arabinan levels remain high for expansion of the cell wall.
“PknA and PknB phosphorylate EmbR85, activating tran- scription of embC, embA and embB81 during growth59,72, thus ensuring that arabinan levels remain high for expan- sion of the cell wall.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
The Regulatory function section (p. 717–731; specific page unavailable) reports that pknB is expressed during active growth and is downregulated under starvation; it also places pknA in the same operon. It does not establish that either kinase phosphorylates EmbR or that this activates embC, embA and embB transcription or maintains arabinan levels. (LLM, conf=0.85)
Experimental — accuracy not yet measured
The transcription of the FAS-I genes fas, accD4 and accD5 seems to correlate with growth.
“The transcrip- tion of the FAS-I genes fas, accD4 and accD5 seems to correlate with growth59,60,88.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
The Lipid biosynthesis section reports that fas, the FAS-I gene, is downregulated in nutrient-starved cultures; Table 3 lists a −3.13-fold change. This is consistent with fas transcription tracking growth in this model, but the cited passages do not establish the claim for accD4 or accD5. (LLM, conf=0.86)
Experimental — accuracy not yet measured
mmaA2 and cmaA1, which catalyse the distal cis cyclopropanations on cis/cis-meromycolates, are downregulated by the stress regulator Rel or by starvation.
“mmaA2 and cmaA1, which catalyse the distal cis cyclopropanations on cis/cis- meromycolates, are downregulated by the stress regula- tor Rel88 or by starvation59.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
The Lipid biosynthesis section reports that cmaA1 and umaA2 are downregulated in starved cultures. It does not name mmaA2 or specify that these enzymes catalyse distal cis cyclopropanation; its description is limited to modification of unsaturated meromycolic acid. The citation attached to this paper supports the starvation finding, not the separate claim about regulation by Rel. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Downregulation of PknA and PknB in stasis should also decrease fbpA and fbpB expression.
“Downregulation of PknA and PknB in stasis59 should also decrease fbpA and fbpB expression65.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
The Lipid biosynthesis section (pp. 717–731) reports that fbpA and fbpB are downregulated in starved cultures. It does not establish that downregulation of PknA and PknB causes or predicts that decrease. (LLM, conf=0.85)
Experimental — accuracy not yet measured

nuo is down-regulated in M. tuberculosis during mouse lung infection, survival in macrophages, NRP-1 and NRP-2, and starvation in vitro.
“Several studies have reported that nuo is down-regulated in M. tuberculosis during mouse lung infection (18), survival in macrophages (19), in both non-replicating persistence (NRP)-1 (1% oxygen saturation) and NRP-2 (0.06% oxygen saturation) relative to aerated mid-log growth (18), and upon starvation in vitro (20).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [20]
LdtA may be upregulated in stasis, and LdtB is required for chronic phase survival.
“Ldta may be upregulated in stasis59, and LdtB is required for chronic phase survival147.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
Several PDIM genes are downregulated during starvation and hypoxia.
“Additionally, several PDIM genes are downregulated during starvation59 and hypoxia108.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
In general, MmpL3 inhibitors are quite effective in both growth and stasis, although this may be because these drugs dissipate the proton motive force, not because of direct activity against MmpL3, which is probably downregulated in stasis.
“in general, these are quite effective in both growth and stasis, although this may be because these drugs dissipate the proton motive force, not because of direct activity against MmpL3 (ref.159), which is probably downregulated in stasis59.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
Citation 59 is attached to the suggestion that MmpL3 is downregulated in stasis, not to the preceding claims about inhibitor efficacy or proton-motive-force dissipation. The Lipid biosynthesis section and the differential-expression table report other genes downregulated during nutrient starvation, but the searched passages do not identify MmpL3 or Rv0206c as downregulated. (LLM, conf=0.72)
Experimental — accuracy not yet measured
FadD32 is highly transcribed in growth and likely downregulated in stasis, so inhibitors of this enzyme are unlikely to be effective in stasis.
“FadD32 is highly transcribed in growth60 and likely downregulated in stasis59, so inhibitors of this enzyme are unlikely to be effective in stasis.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [59]
The Lipid biosynthesis section reports that some genes are downregulated during nutrient starvation, but it does not identify FadD32 among them. Searches for FadD32 and Rv3801c found no passage establishing that this enzyme is downregulated in stasis. The sentence’s conclusion about inhibitor effectiveness is not separately attributed to this source. (LLM, conf=0.72)
Experimental — accuracy not yet measured

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Authors: Betts, J. C., Lukey, P. T., Robb, L. C., McAdam, R. A., & Duncan, K.
Affiliations: GlaxoSmithKline (United Kingdom) (GB)
Corresponding author: Betts, Joanna C.
ORCID: Betts, Joanna C.
Lukey, Pauline T.
Venue: Molecular Microbiology
Publisher: Wiley
Published: 2002-02
Volume: 43
Issue: 3
Pages: 717-731
ISSN: 0950-382X (ISSN-L)
1365-2958
DOI: 10.1046/j.1365-2958.2002.02779.x
OpenAlex: W2125112523
Cited by: 1,395
References: 67
Citations by year: 2026: 35 · 2025: 44 · 2024: 43 · 2023: 47 · 2022: 54 · 2021: 60 · 2020: 64 · 2019: 63 · 2018: 63 · 2017: 60 · 2016: 82 · 2015: 80 · 2014: 74 · 2013: 62 · 2012: 71
FWCI: 30.70
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 27 d)
Locations: Molecular Microbiology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
Keywords: Mycobacterium tuberculosis, bacterial persistence, nutrient deprivation, latent tuberculosis infection, stringent response, gene expression profiling, proteomics, isoniazid resistance, rifampicin resistance, metronidazole resistance, energy metabolism, lipogenesis, transcriptional regulation, therapeutic target
MeSH terms: Adaptation, Physiological, Bacterial Proteins, Cell Membrane, Energy Metabolism, Lipids, Models, Biological, Mycobacterium tuberculosis, Oxygen, Ribosomes, Rifampin, RNA, Bacterial, Transcription, Genetic, Protein Biosynthesis, Electrophoresis, Gel, Two-Dimensional, Gene Expression Regulation, Bacterial, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling

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Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling

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