Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB

Chen, Wenjing; Biswas, Tapan; Porter, Vanessa; Tsodikov, Oleg V.; Garneau‐Tsodikova, Sylvie

doi:10.1073/pnas.1105379108

Cited by 110 publications

(278 citation statements)

References 29 publications

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“…However, they display distinct structural features that may explain the observed functional difference against peptide substrates (as discussed below). While we were preparing this article, the structure of Mtb Eis bound with acetyl CoA was reported by another group (20) [Protein Data Bank (PDB) code 3R1K]. Our structure of acetyl CoA-bound Mtb Eis is highly similar to the reported one, with the rmsds being 0.34 Å for 396 Cα atoms in a monomer (for chains A) and 0.67-0.75 Å for 2,376 Cα atoms in a hexamer.…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidessupporting

confidence: 68%

“…The elongated substratebinding channel in Mtb Eis seems to be suitable not only for accommodating aminoglycosides but also for recognizing the polypeptide substrate in a sequence-specific manner. This channel is also present in the reported structure of Mtb Eis (20). The deep, round-shaped substrate-binding pocket in Msm Eis seems more suitable for accommodating aminoglycosides and the terminal amino group of peptides than sequence-specific recognition of polypeptides.…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 76%

“…Recently Mtb Eis was shown to acetylate multiple amines of many aminoglycosides, including the second-line injectable antituberculosis drugs kanamycin and amikacin (19,20). It was also argued that kanamycin may not be a natural substrate of Mtb Eis because of a high K m value with it (19).…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

“…Increased expression of Mtb Eis due to a mutation in the promoter region of the eis gene conferred resistance to aminoglycoside kanamycin, a second-line antituberculosis drug (19). More recently, Mtb Eis was demonstrated to have an unprecedented ability to acetylate multiple amines of many aminoglycosides, and its reaction mechanism was proposed on the basis of structural and mutational studies (20). However, the fundamental question about the mechanism of enhanced survival of the Msm clone, which contains the extra Mtb eis gene in addition to its own eis gene, still remains unanswered.…”

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confidence: 99%

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Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

Kim¹,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

152

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The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis. Enhanced intracellular survival (Eis) protein, secreted by Mtb, enhances survival of Mycobacterium smegmatis (Msm) in macrophages. Mtb Eis was shown to suppress host immune defenses by negatively modulating autophagy, inflammation, and cell death through JNK-dependent inhibition of reactive oxygen species (ROS) generation. Mtb Eis was recently demonstrated to contribute to drug resistance by acetylating multiple amines of aminoglycosides. However, the mechanism of enhanced intracellular survival by Mtb Eis remains unanswered. Therefore, we have characterized both Mtb and Msm Eis proteins biochemically and structurally. We have discovered that Mtb Eis is an efficient N ɛ -acetyltransferase, rapidly acetylating Lys55 of dualspecificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7), a JNK-specific phosphatase. In contrast, Msm Eis is more efficient as an N α -acetyltransferase. We also show that Msm Eis acetylates aminoglycosides as readily as Mtb Eis. Furthermore, Mtb Eis, but not Msm Eis, inhibits LPSinduced JNK phosphorylation. This functional difference against DUSP16/MKP-7 can be understood by comparing the structures of two Eis proteins. The active site of Mtb Eis with a narrow channel seems more suitable for sequence-specific recognition of the protein substrate than the pocket-shaped active site of Msm Eis. We propose that Mtb Eis initiates the inhibition of JNK-dependent autophagy, phagosome maturation, and ROS generation by acetylating DUSP16/MKP-7. Our work thus provides insight into the mechanism of suppressing host immune responses and enhancing mycobacterial survival within macrophages by Mtb Eis.Rv2416c | lysine acetylation | antituberculosis drug N early one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb). This pathogenic bacterium causes tuberculosis, which claims the lives of millions of people every year (1). Tuberculosis has also become a global health issue owing to the increased incidences of multidrug-resistant and extensively drug-resistant strains of Mtb (2). This makes a search for targets of new antituberculosis drugs urgent. Mtb is a highly successful human pathogen, surviving and multiplying within the human macrophage cells of the infected people (3). Therefore, treatment of tuberculosis is difficult, requiring many months of taking a combination of antibiotics. Mtb has the ability to persist in the form of a long-term asymptomatic infection, referred to as latent tuberculosis (4). Latent tuberculosis becomes activated when the body's immune system is weakened. As a result, tuberculosis is the major cause of death among immuno-compromised AIDS patients (5).In mycobacterial infection, host innate immune responses may play a crucial role in early protection against Mtb infection, leading to establishment of effective adaptive immunity to tuberculosis (6). Additionally, MAPK pathways are activated by Mtb or its components and play an e...

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Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidessupporting

confidence: 68%

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 76%

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

mentioning

confidence: 99%

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Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

Kim¹,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

152

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“…16,17 In addition, kanamycin and capreomycin resistance were conferred by eis and tlyA gene mutations, respectively. 18,19 Saudi Arabia is the third biggest Arab country in the world with a moderate annual TB burden (22 cases/100,000 populations). 2 A moderate level of MDR-TB prevalence (4%) was recently reported with an increasing level of overall resistance (23.6%) to first-line drugs.…”

Section: Introductionmentioning

confidence: 99%

First Insight Into the Fluoroquinolone and Aminoglycoside Resistance of Multidrug-Resistant Mycobacterium tuberculosis in Saudi Arabia

Varghese

Al‐Hajoj

2017

The American Society of Tropical Medicine and Hygiene

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Abstract. In Saudi Arabia, there were no nationwide screening studies conducted so far to determine the aminoglycoside and fluoroquinolone resistance among multidrug-resistant tuberculosis (MDR-TB) isolates. Therefore, as the first attempt in the country, a retrospective analysis has been conducted on a nationwide collection of 2,956 M. tuberculosis clinical isolates screened with phenotypic drug susceptibility testing to define MDR-TB. Enrolled MDR-TB isolates were subjected to second-line drug susceptibility testing, detection of mutations conferring resistance to aminoglycosides and fluoroquinolone, followed by 24-loci mycobacterial interspersed repetitive unitvariable number of tandem repeat typing and spoligotyping. Overall, 83 isolates were identified as MDR-TB, and 13 (15.7%) isolates showed resistance to second-line drugs. Moxifloxacin (low level) showed higher resistant rates (10.8%) followed by ofloxacin (7.2%), capreomycin (3.6%), kanamycin (3.6%), and amikacin (2.4%). Overall fluoroquinolone resistance was 12%, whereas aminoglycoside resistance was 7.2%. Predominant mutations conferring resistance to fluoroquinolone were found in gyrA A90V and D94G, whereas aminoglycoside resistance was observed only with rrs gene A1401G mutation. The corresponding strain lineages predominated with Indo-Oceanic and EastAfrican Indian origin. Interestingly, none of the isolates with second-line drug resistance was defined as extensively drug-resistant TB (XDR-TB). Surprisingly, many isolates (50.6%) were panresistant to first-line drugs. Saudi Arabia faces considerable burden of fluoroquinolone-and aminoglycoside-resistant MDR-TB. Higher incidence of panresistant MDR-TB reveals a threat for the emergence of XDR-TB strains in the near future.

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Antitubercular Agents

Aldrich¹,

Wallis²,

Hegde³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Mycobacterium tuberculosis remains the leading cause of death due to infection in humans. Although antibiotics are available to treat drug‐sensitive M. tuberculosis infections, the increasing incidence of drug‐resistant strains is threatening our ability to gain hold of this pandemic. In addition, recent research has highlighted that even the current standard of care antibiotics face multiple obstacles for reaching therapeutic concentrations at the site of infection. In this article, we detail the current standard of care for clinical tuberculosis (TB) disease, the chemistry, mechanisms of action, and mechanisms of resistance for the antibiotics used clinically to treat TB, the growing problem of antibiotic resistance, and other challenges associated with TB treatment, and host‐directed therapies as an additional approach to treatment. This article is meant to serve as the foundation to build from as the field addresses the dire need for continued development of new therapeutic strategies to treat TB.

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Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB

Cited by 110 publications

References 29 publications

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

First Insight Into the Fluoroquinolone and Aminoglycoside Resistance of Multidrug-Resistant Mycobacterium tuberculosis in Saudi Arabia

Antitubercular Agents

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