scholarly journals Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicholas D. Walter ◽  
Sarah E. M. Born ◽  
Gregory T. Robertson ◽  
Matthew Reichlen ◽  
Christian Dide-Agossou ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Ribosomal Rna ◽  
Molecular Basis ◽  
Drug Effect ◽  
Human Studies ◽  
Effective Drug ◽  
Fundamental Aspect ◽  
Rrna Synthesis ◽  
Bacterial Burden ◽  
Drug Regimens

AbstractThere is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.

scholarly journals Reproducibility of the Ribosomal RNA Synthesis Ratio in Sputum and Association with Markers of Mycobacterium tuberculosis Burden

2021 ◽  
Author(s):  
Emmanuel Musisi ◽  
Christian Dide-Agossou ◽  
Reem Al Mubarak ◽  
Karen Rossmassler ◽  
Abdul Wahab Ssesolo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Ribosomal Rna ◽  
Rna Synthesis ◽  
Rrna Synthesis ◽  
Practical Application ◽  
Pharmacodynamic Marker

This study takes a major next step toward practical application of a novel pharmacodynamic marker that we believe will have transformative implications for tuberculosis. This article follows our recent report in Nature Communications that an assay called the rRNA synthesis (RS) ratio indicates the treatment-shortening of drugs and regimens.

scholarly journals Monkey Models of Tuberculosis: Lessons Learned

2014 ◽  
Vol 83 (3) ◽  
pp. 852-862 ◽  
Author(s):  
Juliet C. Peña ◽  
Wen-Zhe Ho
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Models ◽  
Nonhuman Primates ◽  
Lessons Learned ◽  
Preclinical Testing ◽  
Content Type ◽  
Cynomolgus Macaques ◽  
Drug Regimens

The use of animal models has been invaluable for studying the pathogenesis ofMycobacterium tuberculosisinfection, as well as for testing the efficacy of vaccines and drug regimens for tuberculosis. Among the applied animal models, nonhuman primates, particularly macaques, share the greatest anatomical and physiological similarities with humans. As such, macaque models have been used for investigating tuberculosis pathogenesis and preclinical testing of drugs and vaccines. This review focuses on published major studies which illustrate how the rhesus and cynomolgus macaques have enriched and may continue to advance the field of global tuberculosis research.

Molecular Basis of Drug Resistance in Mycobacterium tuberculosis

2014 ◽  
Vol 2 (3) ◽  
Author(s):  
Keira A. Cohen ◽  
William R. Bishai ◽  
Alexander S. Pym
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Molecular Basis

Timing of Wound Excision

2020 ◽  
pp. 11-14
Keyword(s):  
Surgical Site Infections ◽  
Current Data ◽  
Human Studies ◽  
Bacterial Burden ◽  
Wound Debridement ◽  
The Past ◽  
Severity Of Injury ◽  
Wound Excision ◽  
The Subject ◽  
Intense Debate

The aim of wound excision is to remove contaminating debris and all devitalised tissue. This should reduce both the bacterial burden and available substrate for microbial colonisation, resulting in fewer deep surgical site infections. In turn, this will lead to improved patient outcomes. The timing of wound excision has been the subject of intense debate. In the past, guidelines have favoured wound excision within 6 hours based on historical animal and human studies. Current data suggest that timing of wound debridement should be determined by the degree of contamination and severity of injury.

scholarly journals Revisiting hypoxia therapies for tuberculosis

2019 ◽  
Vol 133 (12) ◽  
pp. 1271-1280 ◽  
Author(s):  
Stefan H. Oehlers
Keyword(s):  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Infectious Diseases ◽  
Industrial Revolution ◽  
Drug Resistant ◽  
Novel Therapies ◽  
Bacterial Burden ◽  
Human History ◽  
Angiogenic Therapy ◽  
Acquired Antibiotic Resistance

Abstract The spectre of the coming post-antibiotic age demands novel therapies for infectious diseases. Tuberculosis (TB), caused by Mycobacterium tuberculosis, is the single deadliest infection throughout human history. M. tuberculosis has acquired antibiotic resistance at an alarming rate with some strains reported as being totally drug resistant. Host-directed therapies (HDTs) attempt to overcome the evolution of antibiotic resistance by targeting relatively immutable host processes. Here, I hypothesise the induction of hypoxia via anti-angiogenic therapy will be an efficacious HDT against TB. I argue that anti-angiogenic therapy is a modernisation of industrial revolution era sanatoria treatment for TB, and present a view of the TB granuloma as a ‘bacterial tumour’ that can be treated with anti-angiogenic therapies to reduce bacterial burden and spare host immunopathology. I suggest two complementary modes of action, induction of bacterial dormancy and activation of host hypoxia-induced factor (HIF)-mediated immunity, and define the experimental tools necessary to test this hypothesis.

scholarly journals Rifampin Resistance in Mycobacterium kansasii Is Associated with rpoB Mutations

2001 ◽  
Vol 45 (11) ◽  
pp. 3056-3058 ◽  
Author(s):  
John L. Klein ◽  
Timothy J. Brown ◽  
Gary L. French
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Basis ◽  
Strong Association ◽  
Missense Mutations ◽  
Β Subunit ◽  
Mycobacterium Kansasii ◽  
Bacterial Rna ◽  
Rifampin Resistance ◽  
Potent Drug

ABSTRACT Rifampin is the most potent drug used in the treatment of disease due to Mycobacterium kansasii. A 69-bp fragment ofrpoB, the gene that encodes the β subunit of the bacterial RNA polymerase, was sequenced and found to be identical in five rifampin-susceptible clinical isolates of M. kansasii. This sequence showed 87% homology with the Mycobacterium tuberculosis gene, with an identical deduced amino acid sequence. In contrast, missense mutations were detected in the same fragment amplified from five rifampin-resistant isolates. A rifampin-resistant strain generated in vitro also harbored an rpoB gene missense mutation that was not present in the parent isolate. All mutations detected (in codons 513, 526, and 531) have previously been described in rifampin-resistant M. tuberculosis isolates. Rifampin MICs determined by E-test were <1 mg/liter for all rifampin-susceptible isolates and >256 mg/liter for all rifampin-resistant ones. In addition, four of the five rifampin-resistant isolates were also resistant to rifabutin. We have thus shown a strong association between rpoB gene missense mutations and rifampin resistance in M. kansasii. Although our results are derived from a small number of isolates and confirmation with larger numbers would be useful, they strongly suggest that mutations within rpoB form the molecular basis of rifampin resistance in this species.

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