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Metallochaperones are needed for mycobacterium tuberculosis and Escherichia coli nicotinamidase-pyrazinamidase activity

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dc.contributor.author Sheen P. es_PE
dc.contributor.author Monsalve A. es_PE
dc.contributor.author Campos J. es_PE
dc.contributor.author Huerta R. es_PE
dc.contributor.author Antiparra R. es_PE
dc.contributor.author Arteaga H. es_PE
dc.contributor.author Duran P. es_PE
dc.contributor.author Bueno C. es_PE
dc.contributor.author Kirwan D.E. es_PE
dc.contributor.author Gilman R.H. es_PE
dc.contributor.author Zimic M. es_PE
dc.date.accessioned 2024-05-30T23:13:38Z
dc.date.available 2024-05-30T23:13:38Z
dc.date.issued 2020
dc.description.abstract Mycobacterium tuberculosis nicotinamidase-pyrazinamidase (PZAse) is a metalloenzyme that catalyzes conversion of nicotinamide-pyrazinamide to nicotinic acid-pyrazinoic acid. This study investigated whether a metallochaperone is required for optimal PZAse activity. M. tuberculosis and Escherichia coli PZAses (PZAse-MT and PZAse-EC, respectively) were inactivated by metal depletion (giving PZAse-MT–Apo and PZAse-EC–Apo). Reactivation with the E. coli metallochaperone ZnuA or Rv2059 (the M. tuberculosis analog) was measured. This was repeated following proteolytic and thermal treatment of ZnuA and Rv2059. The CDC1551 M. tuberculosis reference strain had the Rv2059 coding gene knocked out, and PZA susceptibility and the pyrazinoic acid (POA) efflux rate were measured. ZnuA (200 M) achieved 65% PZAse-EC–Apo reactivation. Rv2059 (1 M) and ZnuA (1 M) achieved 69% and 34.3% PZAse-MT–Apo reactivation, respectively. Proteolytic treatment of ZnuA and Rv2059 and application of three (but not one) thermal shocks to ZnuA significantly reduced the capacity to reactivate PZAse-MT–Apo. An M. tuberculosis Rv2059 knockout strain was Wayne positive and susceptible to PZA and did not have a significantly different POA efflux rate than the reference strain, although a trend toward a lower efflux rate was observed after knockout. The metallochaperone Rv2059 restored the activity of metal-depleted PZAse in vitro. Although Rv2059 is important in vitro, it seems to have a smaller effect on PZA susceptibility in vivo. It may be important to mechanisms of action and resistance to pyrazinamide in M. tuberculosis. Further studies are needed for confirmation. IMPORTANCE Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis and remains one of the major causes of disease and death worldwide. Pyrazinamide is a key drug used in the treatment of tuberculosis, yet its mechanism of action is not fully understood, and testing strains of M. tuberculosis for pyrazinamide resistance is not easy with the tools that are presently available. The significance of the present research is that a metallochaperone-like protein may be crucial to pyrazinamide’s mechanisms of action and of resistance. This may support the development of improved tools to detect pyrazinamide resistance, which would have significant implications for the clinical management of patients with tuberculosis: drug regimens that are appropriately tailored to the resistance profile of a patient’s individual strain lead to better clinical outcomes, reduced onward transmission of infection, and reduction of the development of resistant strains that are more challenging and expensive to treat. Copyright © 2020 Sheen et al.
dc.description.sponsorship Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica - Concytec
dc.identifier.doi https://doi.org/10.1128/JB.00331-19
dc.identifier.scopus 2-s2.0-85077475190
dc.identifier.uri https://hdl.handle.net/20.500.12390/2651
dc.language.iso eng
dc.publisher American Society for Microbiology
dc.relation.ispartof Journal of Bacteriology
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject ZnuA
dc.subject Mechanism of action es_PE
dc.subject Mechanism of resistance es_PE
dc.subject Metal depletion es_PE
dc.subject Metallochaperone es_PE
dc.subject Metalloenzyme es_PE
dc.subject Mycobacterium tuberculosis es_PE
dc.subject Pyrazinamide es_PE
dc.subject Pyrazinoic acid es_PE
dc.subject PZA resistance es_PE
dc.subject Reactivation es_PE
dc.subject Resistance es_PE
dc.subject Rv2059 es_PE
dc.subject.ocde http://purl.org/pe-repo/ocde/ford#3.03.08
dc.title Metallochaperones are needed for mycobacterium tuberculosis and Escherichia coli nicotinamidase-pyrazinamidase activity
dc.type info:eu-repo/semantics/article
dspace.entity.type Publication
oairecerif.author.affiliation #PLACEHOLDER_PARENT_METADATA_VALUE#
oairecerif.author.affiliation #PLACEHOLDER_PARENT_METADATA_VALUE#
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