Abstract
Tuberculosis is once again a major global threat, leading to more than 1 million deaths each year. Treatment options for tuberculosis patients are limited, expensive and characterized by severe side effects, especially in the case of multidrug-resistant forms. Uncovering novel vulnerabilities of the pathogen is crucial to generate new therapeutic strategies. Using high resolution microscopy techniques, we discovered one such vulnerability of Mycobacterium tuberculosis. We demonstrate that the DNA of M. tuberculosis can condense under stressful conditions such as starvation and antibiotic treatment. The DNA condensation is reversible and specific for viable bacteria. Based on these observations, we hypothesized that blocking the recovery from the condensed state could weaken the bacteria. We showed that after inducing DNA condensation, and subsequent blocking of acetylation of DNA binding proteins, the DNA localization in the bacteria is altered. Importantly under these conditions, Mycobacterium smegmatis did not replicate and its survival was significantly reduced. Our work demonstrates that agents that block recovery from the condensed state of the nucleoid can be exploited as antibiotic. The combination of fusidic acid and inhibition of acetylation of DNA binding proteins, via the Eis enzyme, potentiate the efficacy of fusidic acid by 10 and the Eis inhibitor to 1,000-fold. Hence, we propose that successive treatment with antibiotics and drugs interfering with recovery from DNA condensation constitutes a novel approach for treatment of tuberculosis and related bacterial infections.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is the leading cause of death from an infectious disease, resulting in 10.4 million new cases world-wide, including around 500,000 humans infected by the multi-resistant form, and an estimated 1.4 million deaths in 2016 alone (WHO, 2017)
This study focuses on the preservation of bacterial genome integrity by the temporary condensation of chromosomal DNA, a process demonstrated to occur during latency and other stressful conditions in Escherichia coli (Wolf et al, 1999), Bacillus subtilis (Smith et al, 2002), Helicobacter pylori (Ceci et al, 2007), cyanobacteria (Murata et al, 2016), and Deinococcus radiodurans (Eltsov and Dubochet, 2005)
To determine if mycobacteria undergo similar ultrastructural changes, transmission electron microscopy (TEM) was performed on ultrathin sections of early log phase M. smegmatis mc2155 control cultures (OD < 0,8) and cultures treated with the antibiotic fusidic acid (FA)
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is the leading cause of death from an infectious disease, resulting in 10.4 million new cases world-wide, including around 500,000 humans infected by the multi-resistant form, and an estimated 1.4 million deaths in 2016 alone (WHO, 2017). This study focuses on the preservation of bacterial genome integrity by the temporary condensation of chromosomal DNA, a process demonstrated to occur during latency and other stressful conditions in Escherichia coli (Wolf et al, 1999), Bacillus subtilis (Smith et al, 2002), Helicobacter pylori (Ceci et al, 2007), cyanobacteria (Murata et al, 2016), and Deinococcus radiodurans (Eltsov and Dubochet, 2005). Quiescent M. smegmatis with condensed nucleoids display reduced metabolism and increased tolerance to stress and antibiotics (Wu et al, 2016c)
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