A. Farhana, V. Saini, A. Kumar, J. R. Lancaster, and A. J. Steyn, Environmental Heme-Based Sensor Proteins : Implications for Understanding Bacterial Pathogenesis, Antioxidants & Redox Signaling, vol.17, issue.9, pp.1232-1245, 2012.

M. Gilles-gonzalez and G. Gonzalez, Heme-based sensors : defining characteristics, recent developments, and regulatory hypotheses, Journal of Inorganic Biochemistry, vol.99, issue.1, pp.1-22, 2005.

P. L. Carver, The Battle for Iron between Humans and Microbes, Current Medicinal Chemistry, vol.25, issue.1, pp.85-96, 2018.

J. R. Sheldon and D. E. Heinrichs, Recent developments in understanding the iron acquisition strategies of gram positive pathogens, FEMS microbiology reviews, vol.39, issue.4, pp.592-630, 2015.

H. Wikipédia, , 2017.

V. Goff, S. Sennequier, and N. , Biosynthèse du monoxyde d'azote (NO) : mécanisme, régulation et contrôle., Revue médecine/sciences, vol.14, p.1185, 1998.

M. A. Marletta, Nitric oxide synthase : Aspects concerning structure and catalysis, Cell, vol.78, issue.6, pp.927-930, 1994.

J. D. Laskin, D. E. Heck, and D. L. Laskin, Multifunctional role of nitric oxide in inflammation, Trends in Endocrinology &Metabolism, vol.5, issue.9, pp.377-382, 1994.

, Carbon Monoxide Poisoning and Hyperbaric oxygen Therapy, Cancer Care of WESTERN NEW YORK, 2017.

M. P. Soares and F. H. Bach, Heme oxygenase-1 : from biology to therapeutic potential, Science Direct, vol.15, issue.2, pp.50-58, 2009.

G. P. Roberts, H. Youn, and R. L. Kerby, CO-Sensing Mechanisms, Microbiol Mol Biol Rev, vol.68, issue.3, pp.453-473, 2004.

L. K. Wareham, R. Begg, H. E. Jesse, J. W. Van-beilen, S. Ali et al., Carbon Monoxide Gas Is Not Inert, but Global, in Its Consequences for Bacterial Gene Expression, Iron Acquisition, and Antibiotic Resistance, Antioxidants & Redox Signaling, vol.24, issue.17, pp.1013-1028, 2016.

H. Jesse, T. L. Nye, S. Mclean, J. Green, B. E. Mann et al., Cytochrome bd-I in Escherichia coli is less sensitive than cytochromes bd-II or bo?' to inhibition by the carbon monoxide-releasing molecule, CORM-3, Biochim Biophys Acta, vol.1834, issue.9, pp.1693-1703, 2013.

I. Gusarov, K. Shatalin, M. Starodubtseva, and E. Nudler, Endogenous Nitric Oxide Protects Bacteria Against a Wide Spectrum of Antibiotics, Science, vol.325, issue.5946, pp.1380-1384, 2009.

T. Shimizu, The Heme-Based Oxygen-Sensor Phosphodiesterase Ec DOS (DosP) : Structure-Function Relationships, Biosensors, vol.3, issue.2, pp.211-237, 2013.

M. David, M. L. Daveran, J. Batut, A. Dedieu, O. Domergue et al., Cascade regulation of nif gene expression in Rhizobium meliloti, Cell, vol.54, issue.5, pp.671-83, 1988.

S. Aono, T. Matsuo, T. Shimono, K. Ohkubo, H. Takasaki et al., Single transduction in the transcriptional activator CooA containing a heme-Based CO Sensor : isolation of a dominant positive mutant which is active as the transcriptional activator even in the absence of CO, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol.240, pp.783-786, 1997.

D. Shelver, R. Kerby, Y. L-;-he, and G. P. Roberts, Carbon monoxide-induced activation of gene expression in Rhodospirillum rubrum requires the product of cooA, a member of the cyclic AMP receptor protein family of transcrtional regulators, J Bacteriol, vol.177, issue.8, pp.2157-63, 1995.

L. M. Iyer, V. Anantharaman, and L. Aravind, Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins, BMC Genomics, vol.3, issue.1, p.5, 2003.

D. S. Karow, D. Pan, R. Tran, P. Pellicena, A. Presley et al., Spectroscopic Characterization of the Soluble Guanylate Cyclase-like Heme Domains from Vibrio cholerae and Thermoanaerobacter tengcongensis, Biochemistry, vol.43, pp.10203-10211, 2004.

J. B. Stock, A. J. Ninfa, and A. M. Stock, Protein phosphorylation and regulation of adaptive responses in bacteria, Microbiol Rev, vol.53, pp.450-90, 1989.

M. A. Gilles-gonzalez, G. S. Ditta, and D. R. Helinski, A haemoprotein with kinase activity encoded by the oxygen sensor of Rhizobium meliloti, Nature, pp.170-172, 1991.

J. R. Tuckerman, G. Gonzalez, E. M. Dioum, and M. A. Gilles-gonzalez, Ligand and oxidationstate specific regulation of the heme-based oxygen sensor FixL from Sinorhizobium meliloti, Biochemistry, issue.19, pp.6170-6177, 2002.

W. Gong, B. Hao, S. S. Mansy, G. Gonzalez, M. A. Gilles-gonzalez et al., Structure of a biological oxygen sensor : A new mechanism for heme-driven signal transduction, Proceedings of the National Academy of Sciences, vol.95, issue.26, pp.15177-15182, 1998.

J. L. Pellequer, R. Brudler, and E. D. Getzoff, Biological sensors: More than one way to sense oxygen -Curr Biol, vol.9, pp.416-424, 1999.

X. Ma, N. Sayed, A. Beuve, and F. Van-den-akker, NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism, The EMBO Journal, vol.26, issue.2, pp.578-88, 2007.

J. Hardman and E. W. Sutherland, Guanyl cyclase, an enzyme catalyzing the formation of guanosine 3',5'-monophosphate from guanosine trihosphate, J Biol Chem, vol.244, issue.23, pp.6363-70, 1969.

D. S. Karow, D. Pan, J. H. Davis, S. Behrends, R. S. Mathies et al., A : Characterization of Functional Heme Domains from Soluble Guanylate Cyclase, Biochemistry, vol.44, issue.49, pp.16266-16274, 2005.

J. W. Denninger and M. A. Marletta, Guanylate cyclase and the ?NO/cGMP signaling pathway, Biochimica et Biophysica Acta (BBA) -Bioenergetics, vol.1411, pp.334-350, 1999.

S. Moncada and A. Higgs, Nitric Oxide : Role in Human Disease, ENCYCLOPEDIA OF LIFE SCIENCES, 2003.

F. Seeger and E. D. Garcin, Soluble guanylate cyclase crystal clear : 1st crystal structure of the wild-type human heterodimeric sGC catalytic domains and implications for activity, BMC Pharmacology Toxicology, issue.14, p.14, 2013.

E. M. Dioum, J. Rutter, J. S. Tuckerman, G. Gonzalez, M. A. Gilles-gonzalez et al., NPAS2 : A Gas-Responsive Transcription Factor, vol.298, pp.2385-2387, 2002.

W. N. Lanzilotta, D. J. Schuller, M. V. Thorsteinsson, R. L. Kerby, G. P. Roberts et al., Structure of the CO sensing transcription activator CooA, Nature Structural Biology, vol.7, issue.10, p.876, 2000.

R. Tenhunen, H. S. Marver, and R. Schmid, Microsomal Heme Oxygenase, Journal of Biological Chemistry, pp.6388-6394, 1969.

J. Wang and P. R. Montellano, The Binding Sites on Human Heme Oxygenase-1 for Cytochrome P450 Reductase and Biliverdin Reductase, Journal of Biological Chemistry, 2003.

H. Nishino and T. Ishibashi, Evidence for Requirement of NADPH-Cytochrome P450

, Oxidoreductase in the Microsomal NADPH-Sterol ?7-Reductase System, vol.374, pp.293-298, 2000.

D. Boehning and S. H. Snyder, Carbon Monoxide and Clocks, vol.298, pp.2339-2340, 2002.

S. Minegishi, I. Sagami, S. Negi, K. Kano, and H. Kitagishi, Circadian clock disruption by selective removal of endogenous carbon monoxide, Scientific Reports, vol.8, p.11996, 2018.

M. Puranik, S. B. Nielsen, H. Youn, A. N. Hvitved, J. L. Bourassa et al., Dynamics of Carbon Monoxide Binding to CooA, Journal of Biological Chemistry, vol.279, issue.20, pp.21096-21108, 2004.

R. L. Kerby, P. W. Ludden, and G. P. Roberts, Carbon monoxide-dependent growth of Rhodospirillum rubrum, Journal of Bacteriology, vol.177, issue.8, pp.2241-2244, 1995.

M. V. Thorsteinsson, R. L. Kerby, M. Conrad, H. Youn, C. R. Staples et al., Characterization of Variants Altered at the N-terminal Proline, a Novel Heme-Axial Ligand in CooA, the CO-sensing Transcriptional Activator, Journal of Biological Chemistry, vol.275, issue.50, pp.39332-39338, 2000.

M. K. Chan, CooA, CAP and allostery, Nature Structural Biology, vol.7, pp.822-824, 2000.

M. Borjigin, H. Li, N. D. Lanz, R. L. Kerby, G. P. Roberts et al., Structure-based hypothesis on the activation of the CO-sensing transcription factor CooA, Acta Crystallographica Section D : Biological Crystallography, vol.63, issue.3, pp.282-287, 2007.

U. Liebl, J. Lambry, and M. H. Vos, Primary processes in heme-based sensor proteins, Biochimica et Biophysica Acta (BBA) -Proteins and Proteomics, issue.9, pp.1684-1692, 2012.
URL : https://hal.archives-ouvertes.fr/hal-00817153

R. L. Kerby, H. Youn, and G. Roberts, RcoM : A New Single-Component Transcriptional Regulator of CO Metabolism in Bacteria, Journal Bacteriology, vol.190, issue.9, pp.3336-3343, 2008.

R. L. Kerby and G. P. Roberts, Burkholderia xenovorans RcoMBx-1, a Transcriptional Regulator System for Sensing Low and Persistent Levels of Carbon Monoxide, Journal of Bacteriology, vol.194, issue.21, pp.5803-5816, 2012.

, A Unique CO-sensing Transcription Factor, RcoM -Burstyn Lab (Research Overview) -The UW-Madison Heme team

K. A. Marvin, R. L. Kerby, H. Youn, G. P. Roberts, and J. N. Burstyn, The transcription regulator RcoM-2 from Burkholderia xenovorans is a cysteine-ligated hemoprotein that undergoes a redoxmediated ligand switch, Biochemistry, vol.47, issue.34, pp.9016-9028, 2008.

L. Bouzhir-sima, R. Motterlini, J. Gross, M. V. Vos, and U. Liebl, Unusual Dynamics of Ligand Binding to the Heme Domain of the Bacterial CO Sensor Protein RcoM-2, The Journal of Physical Chemistry, B, pp.10686-10694, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01612915

A. Benabbas, V. Karunakaran, H. Youn, T. L. Poulos, and P. M. Champion, Effect of DNA Binding on Geminate CO Recombination Kinetics in CO-sensing Transcription Factor CooA, The Journal of Biological Chemistry, vol.287, issue.26, pp.21729-21740, 2012.

K. Floyd, P. Glaziou, A. Zumla, and M. Raviglione, The global tuberculosis epidemic and progress in care, prevention, and research : an overview in year 3 of the End TB era, The Lancet Respiratory Medicine, vol.6, issue.4, pp.299-314, 2018.

V. Dartois, The path of anti-tuberculosis drugs : from blood to lesions to mycobacterial cells, Nature reviews. Microbiology, vol.12, issue.3, pp.159-167, 2014.

S. T. Cole, R. Brosch, J. Parkhill, T. Garnier, C. Churcher et al., Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence, Nature, issue.6685, p.537, 1998.

A. Koul, E. Arnoult, N. Lounis, J. Guillemont, and K. Andries, The challenge of new drug discovery for tuberculosis, Nature, issue.7331, pp.483-490, 2011.

M. Gengenbacher and S. H. Kaufmann, Mycobacterium tuberculosis : Success through dormancy, Fems Microbiology Reviews, vol.36, issue.3, pp.514-532, 2012.

C. Nathan and M. U. Shiloh, Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens, Proceedings of the National Academy of Sciences of the United States of America, vol.97, pp.8841-8848, 2000.

R. Tenhunen, H. S. Marver, and R. Schmid, The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase, Proceedings of the National Academy of Sciences of the United States of America, pp.748-755, 1968.

V. M. Zacharia and M. U. Shiloh, Effect of carbon monoxide on Mycobacterium tuberculosis pathogenesis, Medical Gas Research, vol.2, p.30, 2012.

S. Brouard, L. E. Otterbein, J. Anrather, E. Tobiasch, F. H. Bach et al., Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis, The Journal of Experimental Medicine, vol.192, issue.7, pp.1015-1026, 2000.

J. Sun, H. Hoshino, K. Takaku, O. Nakajima, A. Muto et al., Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene, The EMBO Journal, vol.21, issue.19, pp.5216-5224, 2002.

E. Balogun, M. Hoque, P. Gong, E. Killeen, C. J. Green et al., Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidantresponsive element, Biochemical Journal, vol.371, pp.887-895, 2003.

J. Alam, D. Stewart, C. Touchard, S. Boinapally, A. M. Choi et al., Nrf2, a Cap'n'Collar Transcription Factor, Regulates Induction of the Heme Oxygenase-1 Gene, Journal of Biological Chemistry, vol.274, issue.37, pp.26071-26078, 1999.

R. Motterlini and R. Foresti, Heme Oxygenase-1 As a Target for Drug Discovery, Antioxidants & Redox Signaling, vol.20, issue.11, pp.1810-1826, 2013.

M. I. Voskuil, D. Schnappinger, K. C. Visconti, M. I. Harrell, G. M. Dolganov et al., Inhibition of Respiration by Nitric Oxide Induces a Mycobacterium tuberculosis Dormancy Program, The Journal of Experimental Medicine, vol.198, issue.5, pp.705-713, 2003.

H. Park, K. M. Guinn, M. I. Harrell, R. Liao, M. I. Voskuil et al., Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis, Molecular microbiology, vol.48, issue.3, pp.833-843, 2003.

D. M. Roberts, R. P. Liao, G. Wisedchaisri, W. G. Hol, and D. R. Sherman, Two Sensor Kinases Contribute to the Hypoxic Response of Mycobacterium tuberculosis, The Journal of biological chemistry, vol.279, issue.22, pp.23082-23087, 2004.

H. He, R. Hovey, J. Kane, V. Singh, and T. C. Zahrt, MprAB is a stress-responsive twocomponent system that directly regulates expression of sigma factors SigB and SigE in Mycobacterium tuberculosis, Journal of Bacteriology, vol.188, issue.6, pp.2134-2143, 2006.

A. Kumar, J. C. Toledo, R. P. Patel, J. R. Lancaster, and A. J. Steyn, Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor, Proceedings of the National Academy of Sciences of the United States of America, vol.104, issue.28, pp.11568-11573, 2007.

A. Gerasimova, A. E. Kazakov, A. P. Arkin, I. Dubchak, and M. S. Gelfand, Comparative genomics of the dormancy regulons in mycobacteria, J Bacteriol, vol.193, issue.14, pp.3446-52, 2011.

S. Sivaramakrishnan and P. R. De-montellano, The DosS-DosT/DosR Mycobacterial Sensor System, Biosensors, vol.3, issue.3, pp.259-282, 2013.

D. R. Sherman, M. Voskuil, D. Schnappinger, R. Liao, M. I. Harrell et al., Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding ?-crystallin, Proceedings of the National Academy of Sciences of the United States of America, vol.98, pp.7534-7539, 2001.

H. Yang, W. Sha, Z. Liu, T. Tang, H. Liu et al., Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis, Emerging Microbes & Infections, vol.7, p.34, 2018.

M. Rv0081 and D. , Mycobacterium tuberculosis, vol.193, pp.5105-5118, 2011.

X. Sun, L. Zhang, J. Jiang, M. Ng, Z. Cui et al., Transcription factors Rv0081 and Rv3334 connect the early and the enduring hypoxic response of Mycobacterium tuberculosis, vol.9, pp.1468-1482, 2018.

D. R. Campbell, K. E. Chapman, K. J. Waldron, S. Tottey, S. Kendall et al., Mycobacterial Cells Have Dual Nickel-Cobalt Sensors, vol.282, pp.32298-32310, 2007.

A. Kumar, S. Phulera, A. Rizvi, P. Sonawane, H. S. Panwar et al., Structural basis of hypoxic gene regulation by the Rv0081 transcription factor of Mycobacterium tuberculosis, bioRxiv, p.465575, 2018.

J. E. Galagan, K. Minch, M. Peterson, A. Lyubetskaya, E. Azizi et al., The Mycobacterium tuberculosis regulatory network and hypoxia, pp.178-183, 2013.

V. M. Zacharia, P. S. Manzanillo, V. R. Nair, D. K. Marciano, L. N. Kinch et al., cor, a Novel Carbon Monoxide Resistance Gene, Is Essential for Mycobacterium tuberculosis Pathogenesis, pp.721-734, 2013.

M. K. You, H. Y. Shin, Y. J. Kim, S. H. Ok, S. K. Cho et al., Novel Bifunctional Nucleases, OmBBD and AtBBD1, Are Involved in Abscisic Acid-Mediated Callose Deposition in Arabidopsis, Plant Physiology, vol.152, issue.2, pp.1015-1029, 2010.

S. Singh, R. R. Sevalkar, D. Sarkar, and S. Karthikeyan, Characteristics of the essential pathogenicity factor Rv1828, a MerR family transcription regulator from Mycobacterium tuberculosis, The FEBS Journal, vol.285, issue.23, pp.4424-4444, 2018.

N. L. Brown, J. V. Stoyanov, S. P. Kdd, and J. L. Hobman, The MerR family of transcriptional regulators, FEMS Microbiology Reviews, vol.27, pp.145-163, 2003.

M. A. Pennella and D. P. Giedroc, Structural Determinants of Metal Selectivity in Prokaryotic Metal-responsive transcriptional Regulators, vol.18, pp.413-441, 2005.

M. Ventura, B. Rieck, F. Boldrin, G. Degiacomi, M. Bellinzoni et al., GarA is an essential regulator of metabolism in Mycobacterium tuberculosis, Molecular Microbiology, vol.90, issue.2, pp.356-366, 2013.

L. Lobato, L. Bouzhir-sima, T. Yamashita, M. T. Wilson, M. H. Vos et al., Dynamics of the heme-binding bacterial gas-sensing dissimilative nitrate respiration regulator (DNR) and activation barriers for ligand binding and escape, The Journal of Biological Chemistry, vol.289, issue.38, pp.26514-26524, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01079002

M. Reichlin, Hemoglobin and Myoglobin in Their Reactions with Ligands. Eraldo Antonini and Maurizio Brunori, illus. Frontiers of Biology, vol.21, 1971.

M. H. Vos, A. Battistoni, C. Lechauve, M. C. Marden, L. Kiger et al., Ultrafast heme-residue bond formation in six-coordinate heme proteins : implications for functional ligand exchange, Biochemistry, vol.47, issue.21, pp.5718-5723, 2008.
URL : https://hal.archives-ouvertes.fr/inserm-00292529

R. Ménard, P. J. Sansonetti, and C. Parsot, Nonpolar mutagenesis of the ipa genes defines IpaB, IpaC, and IpaD as effectors of Shigella flexneri entry into epithelial cells, Journal of Bacteriology, vol.175, issue.18, pp.5899-5906, 1993.

F. W. Studier and B. A. Moffatt, Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes, Journal of Molecular Biology, vol.189, issue.1, pp.113-130, 1986.

L. Lobato, Internal dynamics of heme-based sensor proteins studied using advanced timeresolved optical spectroscopy, p.127, 2013.
URL : https://hal.archives-ouvertes.fr/pastel-00866894

G. Joyce, B. D. Robertson, and K. J. Williams, A modified agar pad method for mycobacterial live-cell imaging, BMC Research Notes, vol.4, issue.1, p.73, 2011.

T. Shimizu, D. Huang, F. Yan, M. Stranava, M. Bartosova et al., Gaseous O 2 , NO, and CO in Signal Transduction: Structure and Function Relationships of Heme-Based Gas Sensors and Heme-Redox Sensors, Chem. Rev, vol.115, pp.6491-6533, 2015.

M. Ne?rerie, Iron transitions during activation of allosteric heme proteins in cell signaling, Metallomics, vol.11, pp.868-893, 2019.

J. Boczkowski, J. J. Poderoso, and R. Motterlini, COmetal interaction: vital signaling from a lethal gas, Trends Biochem. Sci, vol.31, pp.614-621, 2006.

F. Gullotta, A. Di-masi, M. Coletta, A. , and P. , CO metabolism, sensing, and signaling, Biofactors, vol.38, pp.1-13, 2012.

S. H. Heinemann, T. Hoshi, M. Westerhausen, and A. Schiller, Carbon monoxide -physiology, detection and controlled release, Chem. Commun, vol.50, pp.3644-3660, 2014.

H. Kim, S. Ryter, and A. Choi, CO as a cellular signalling molecule, Annu. Rev. Pharmacol. Toxicol, vol.46, pp.411-449, 2006.

E. M. Dioum, J. Rutter, J. R. Tuckerman, G. Gonzalez, M. Gilles-gonzalez et al., NPAS2: A Gas-Responsive Transcription Factor, Science, vol.298, pp.2385-2387, 2002.

S. M. Kapetanaki, M. J. Burton, J. Basran, C. Uragami, P. C. Moody et al., A mechanism for CO regulation of ion channels, Nat. Commun, vol.9, p.907, 2018.
URL : https://hal.archives-ouvertes.fr/cea-01876610

P. Ascenzi, A. Bocedi, L. Leoni, P. Visca, E. Zennaro et al., CO Sniffing through Heme-based Sensor Proteins, IUBMB Life, vol.56, pp.309-315, 2004.

W. N. Lanzilotta, D. J. Schuller, M. V. Thorsteinsson, R. L. Kerby, G. P. Roberts et al., Structure of the CO sensing transcription activator CooA, Nat. Struct. Biol, vol.7, pp.876-880, 2000.

R. L. Kerby, H. Youn, and G. P. Roberts, RcoM: A New Single-Component Transcriptional Regulator of CO Metabolism in Bacteria, J. Bacteriol, vol.190, pp.3336-3343, 2008.

L. Bouzhir-sima, R. Motterlini, J. Gross, M. H. Vos, and U. Liebl, Unusual Dynamics of Ligand Binding to the Heme Domain of the Bacterial CO Sensor Protein RcoM-2, J. Phys. Chem. B, vol.120, pp.10686-10694, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01612915

H. E. Bowman, M. R. Dent, and J. N. Burstyn, Met104 is the CO-replaceable ligand at Fe(II) heme in the CO-sensing transcription factor BxRcoM-1. JBIC, J. Biol. Inorg. Chem, vol.21, pp.4028-4034, 2016.

R. L. Kerby and G. P. Roberts, Burkholderia xenovorans RcoMBx-1, a Transcriptional Regulator System for Sensing Low and Persistent Levels of Carbon Monoxide, J. Bacteriol, vol.194, pp.5803-5816, 2012.

K. A. Marvin, R. L. Kerby, H. Youn, G. P. Roberts, and J. N. Burstyn, The Transcription Regulator RcoM-2 from Burkholderia xenovorans Is a Cysteine-Ligated Hemoprotein That Undergoes a Redox-Mediated Ligand Switch, Biochemistry, vol.47, pp.9016-9028, 2008.

A. T. Smith, K. A. Marvin, K. M. Freeman, R. L. Kerby, G. P. Roberts et al., Identification of Cys94 as the distal ligand to the Fe(III) heme in the transcriptional regulator RcoM-2 from Burkholderia xenovorans, J. Biol. Inorg. Chem, vol.17, pp.1071-1082, 2012.

R. C. Pinhancos, H. E. Bowman, M. R. Dent, B. H. Young, C. E. Berndsen et al., The Heme-Binding PAS Domain Mediates Dimerization in the CO-Sensing Transcription Factor BxRcoM-1, FASEB J, vol.31, p.15, 2017.

L. Lobato, L. Bouzhir-sima, T. Yamashita, M. T. Wilson, M. H. Vos et al., Dynamics of the heme-binding bacterial gas sensing dissimilative nitrate respiration regulator (DNR) and activation barriers for ligand binding and escape, J. Biol. Chem, vol.289, pp.26514-26524, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01079002

E. Antonini and M. Brunori, Hemoglobin and Myoglobin in Their Reactions with Ligands, 1971.

C. Creze, A. Ligabue, S. Laurent, R. Lestini, S. P. Laptenok et al., Modulation of the Pyrococcus abyssi NucS endonuclease activity by the replication clamp PCNA at functional and structural levels, J. Biol. Chem, vol.287, pp.15648-15660, 2012.

R. Copeland, Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis, 2004.

S. P. Laptenok, L. Bouzhir-sima, J. Lambry, H. Myllykallio, U. Liebl et al., Ultrafast real time visualization of the active site flexibility of the flavoenzyme thymidylate synthase ThyX, Proc. Natl. Acad. Sci. U. S. A, vol.110, pp.8924-8929, 2013.

G. Silkstone, A. Jasaitis, M. T. Wilson, and M. H. Vos, Ligand dynamics in an electron-transfer protein: picosecond geminate recombination of carbon monoxide to heme in mutant forms of cytochrome c, J. Biol. Chem, vol.282, pp.1638-1649, 2007.
URL : https://hal.archives-ouvertes.fr/hal-00097190

M. H. Vos, Ultrafast dynamics of ligands within heme proteins, Biochim. Biophys. Acta, Bioenerg, vol.1777, pp.15-31, 2008.
URL : https://hal.archives-ouvertes.fr/hal-00324230

A. Benabbas, V. Karunakaran, H. Youn, T. L. Poulos, and P. M. Champion, Effect of DNA Binding on Geminate CO Recombination Kinetics in CO-sensing Transcription Factor CooA, J. Biol. Chem, vol.287, pp.21729-21740, 2012.

V. M. Delgado-nixon, G. Gonzalez, and M. A. Gilles-gonzalez, Dos, a heme-binding PAS protein from Escherichia coli, is a direct oxygen sensor, Biochemistry, vol.39, pp.2685-2691, 2000.

S. Taguchi, T. Matsui, J. Igarashi, Y. Sasakura, Y. Araki et al., Binding of Oxygen and Carbon Monoxide to a Heme-regulated Phosphodiesterase from Escherichia coli: Kinetics and Infrared Spectra of the Full-Length Wild-Type Enzyme, 2004.

, Mutants. J. Biol. Chem, vol.279, pp.3340-3347

U. Liebl, L. Bouzhir-sima, L. Kiger, M. C. Marden, J. Lambry et al., Ligand binding dynamics to the heme domain of the oxygen sensor Dos from Escherichia coli, Biochemistry, vol.42, pp.6527-6535, 2003.
URL : https://hal.archives-ouvertes.fr/hal-00836433

Y. Ishitsuka, Y. Araki, A. Tanaka, J. Igarashi, O. Ito et al., Arg97 at the Heme-Distal Side of the Isolated Heme-Bound PAS Domain of a Heme-Based Oxygen Sensor from Escherichia coli (Ec DOS) Plays Critical Roles in Autoxidation and Binding to Gases, Particularly O 2, Biochemistry, vol.47, pp.8874-8884, 2008.

C. Lechauve, L. Bouzhir-sima, T. Yamashita, M. C. Marden, M. H. Vos et al., Heme Ligand Binding Properties and Intradimer Interactions in the Full-length Sensor Protein Dos from Escherichia coli and Its Isolated Heme Domain, J. Biol. Chem, vol.284, pp.36146-36159, 2009.
URL : https://hal.archives-ouvertes.fr/hal-00811678

M. Puranik, S. B. Nielsen, H. Youn, A. N. Hvitved, J. L. Bourassa et al., Dynamics of Carbon Monoxide Binding to CooA, 2004.

, J. Biol. Chem, vol.279, pp.21096-21108

S. Dewilde, L. Kiger, T. Burmester, T. Hankeln, V. Baudin-creuza et al.,

, Biochemical Characterization and Ligand Binding Properties of Neuroglobin, a Novel Member of the Globin Family, J. Biol. Chem, vol.276, pp.38949-38955

S. Kumazaki, H. Nakajima, T. Sakaguchi, E. Nakagawa, H. Shinohara et al., Dissociation and recombination between ligands and heme in a CO-sensing transcriptional activator CooA, J. Biol. Chem, vol.275, pp.38378-38383, 2000.

S. Abbruzzetti, S. Faggiano, S. Bruno, F. Spyrakis, A. Mozzarelli et al., Ligand migration through the internal hydrophobic cavities in human neuroglobin, Proc. Natl. Acad. Sci. U. S. A, vol.106, pp.18984-18989, 2009.

M. Milani, A. Pesce, M. Nardini, H. Ouellet, Y. Ouellet et al., Structural bases for heme binding and diatomic ligand recognition in truncated hemoglobins, J. Inorg. Biochem, vol.99, pp.97-109, 2005.

C. F. Weber and G. M. King, The phylogenetic distribution and ecological role of carbon monoxide oxidation in the genus Burkholderia, FEMS Microbiol. Ecol, vol.79, pp.167-175, 2012.

J. P. Hines, M. R. Dent, D. J. Stevens, and J. N. Burstyn, Site-directed spin label electron paramagnetic resonance spectroscopy as a probe of conformational dynamics in the Fe(III) "locked-off " state of the CO-sensing transcription factor CooA, Protein Sci, vol.27, pp.1670-1679, 2018.

M. V. Thorsteinsson, R. L. Kerby, M. Conrad, H. Youn, C. R. Staples et al., Characterization of Variants Altered at the N-terminal Proline, a Novel Heme-Axial Ligand in CooA, the CO-sensing Transcriptional Activator, J. Biol. Chem, vol.275, pp.4028-4034, 2000.

J. Modranka and +. , Anastasia Parchina +

;. Shrinivas-dumbre, ;. Salman, F. Hubert, . Becker-;-roeland, and . Vanhoutte, Hannu Myllykallio

J. Rozenski,

.. J. Dr, . Modranka, . J. Dr, . Li, . A. Dr et al., Prof. E. Lescrinier Medicinal Chemistry, vol.49

.. M. Dr, . Salman, .. H. Prof, and . Myllykallio, Prof. H. F. Becker Laboratory of Optics and Biosciences, INSERM U 696-CNRS UMR 7645, 91128.

. H. Prof, Becker FacultØ des Sciences et IngØnierie, Sorbonne UniversitØ, 4 place Jussieu 75005

.. S. Dr and . De, Jonghe Present affiliation: Laboratory of Virology and Chemotherapy, Herestraat, vol.49

R. , Vanhoutte Present affiliation: Laboratory of Chemical Biology, KU Leuven, O&N I, Herestraat 49, PO Box, vol.802

, Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under

H. Nmr,

, 6.93 (t, J = 7.2 Hz, H, CH), 7.33 (t, J = 7.55 Hz, 2 H, 2CH), 7.45 (d

, (3H)-yl)propanoyl)-N-phenylpiperazine-1-carboxamide (17 a): A mixture of 6-chloro-2H-benzo

, Cl 2 (100 mL) and washed with H 2 O (40 mL), dried over Na 2 SO 4 , concentrated and purified by flash column chromatography to afford the title compound (318 mg, 72 %). Purity (Method A): 95.86 %. 1 H NMR (300 MHz

. Mhz, CDCl 3 ): d = 30, vol.69

. Hrms-(esi,

H. Nmr, 58 (s, 2 H, O-CH 2 -CO), 4.23 (t, 2 H, 300 MHz, CDCl 3 ): d = 7.1-6.95 (m, 4 H), vol.4

C. Nmr,

+. ,

. Hz, ppm (t, 2 H, J = 7.5 Hz, N-CH 2 -CH 2 ), vol.13

. Mhz,

, Oxo-3-(piperazin-1-yl)propyl)-2H-benzo

, MeOH/NH 3(aq) in a ratio of 98:2:0.3), to yield the title compound as a light-yellow oil (0.4 g, 31 %). 1 H NMR (300 MHz

. Mhz,

, CDCl 3 ): d = 7.40 (s, 1 H), 7.30-6.93 (m, 8 H), 4.57 (s, 2 H, O-CH 2 -CO, Purity (Method A): 99.83 %. 1 H NMR (300 MHz

. Mhz, , vol.8, p.30

, HRMS (ESI)

, Oxo-2,3-dihydro-4H-benzo, vol.27

/. Meoh and . Nh, 92:8:0.3). DIPEA (42an off-white solid (28 mg, 32 %), Purity (Method A, vol.3

, CDCl 3 ): d = 8.38-8.32 (m, 2 H), vol.7

, 57 (s, 2 H, O-CH 2 -CO), 4.24 (t, 2 H, J = 7.6 Hz, N-CH 2 -CH 2 -CO, vol.4

, Compound 28 was synthesized according to the procedure for the preparation of compound 27. Exact experimental and spectral data can be found in the Supporting Information. 2-(4-(3-(3-Oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoyl)piperazin-1-yl)-N-(pyridin-3-yl)acetamide (29 a): To a solution of 2-(piperazin-1-yl)-N-(pyridin-3-yl)acetamide (110 mg, 0.5 mmol) in DMSO (10 mL) was added compound 20 (110 mg 0.50 mmol), HCTU (206 mg 0.5 mmol) and DIPEA (50 mL). The reaction mixture was stirred overnight at room temperature. Then, the mixture was diluted with CH 2 Cl 2 (100 mL) and washed with H 2 O (40 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo, HRMS (ESI): m/z [M + H] + calculated for C 21 H 24 N 5 O 4 410.18226, found 410.1817

T. and J. , 19 (s, 2 H, CH 2 ), 3.56-3.58 (m, 2 H, (m, 4 H, 4CH), 7.27-7.31(m, 1 H, 1CH), 8.19-8.23 (m, 1 H, 1CH), 8.32-8.37 (m, 1 H, 1CH), 8.59 (d, J = 2.4 Hz, H, CH), 9.05 ppm, vol.3

, 00 g, 33.52 mmol) and K 2 CO 3 (13.90 g, 100.57 mmol) were dissolved in DMF (80 mL) and stirred at room temperature for 15 min. Then, ethyl bromoacetate (11.20 g, 67 mmol) was added and the reaction mixture was stirred overnight at 90 8C. The solvents were evaporated in vacuo and the residue was purified by silica gel column chromatography (using a mixture of cyclohexane and EtOAc in a ratio of 7:3 as mobile phase) affording the title compound as a colorless oil (7.70 g, 98 %). 1 H NMR (300 MHz, CDCl, vol.18, issue.5

, 1 H NMR (300 MHz, DMSO): d = 13.09 (br s, 1 H), 7.10-6.95 (m

, ChemMedChem, vol.14, pp.1-19, 2019.

-. Wiley, &. Gmbh, . Co, and . Kgaa, Weinheim 4-(2-Oxo-2-(piperazin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (30''): 2-(3-Oxo-2,3-dihydro-4H-benzo, 2019.

H. Nmr, 300 MHz, DMSO): d = 7.07-6.98 (m, 3 H), vol.6

, m, 2 H), 3.42-3.36 (m, 2 H), 2.84-2.77 (m, 2 H), 2.73-2.66 ppm (m, 2 H

, HRMS (ESI)

, Compound 32 was synthesized according to the procedure described for the synthesis of compound 22 a, affording the title compound as a white powder (89 mg, 89 %). Purity (Method A): 98.76 %. 1 H NMR (300 MHz, CDCl 3 ): d = 7.40-7.25 (m, 3 H), 7.10-6.95 (m, 4 H)

, HRMS (ESI)

, 3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propyl)-Nphenylpiperazine-1-carboxamide (39): A mixture of 2H-benzo

, Purity (Method A): 98.85 %. 1 H NMR (300 MHz, vol.101, pp.33-40

, CDCl 3 ): d = 24, vol.41

, 4-Diazepan-1-yl)-3-oxopropyl)-2H-benzo

, Cl 2 /MeOH/ NH 3 (aq) 92:8:0.3), to yield the title compound as a light-yellow oil (0.506 g, 46 %). 1 H NMR (300 MHz, reaction mixture was stirred overnight at room temperature. The precipitate was filtered off and washed with CH 2 Cl 2 . The filtrate was evaporated and the residue was purified by silica gel flash chromatography (the mobile phase being CH 2, vol.6, pp.98-104

, This compound was synthesized from compound 40, according to the procedure for the synthesis of compound 22 a. The crude residue was purified by silica gel flash chromatography (using EtOAc as mobile phase), to yield the title compound as a white powder (93 % yield), Purity (Method A, issue.3

, (m, 2 H), 2.75-2.65 (m, 1.98 ppm

, mmol) was dissolved in THF (10 mL) and a solution of phenylisocyanate (60 mg 0.57 mmol) in THF (5 mL) was slowly added at room temperature. A light-yellow solid was formed upon reaction completion. Then, trifluoroacetic acid (10 mL) was added dropwise while stirring at 0 8C. When TLC showed completion of the deprotection, the mixture was diluted with H 2 O (50 mL). Then, the mixture was washed with CH 2 Cl 2 (30 mL) and the aqueous phase was adjusted to pH 9 by the addition of 1 n NaOH. The mixture was extracted with CH 2 Cl 2 (50 mL). The combined organic layers were dried over Na 2 SO 4 . The solvents were evaporated in vacuo, affording crude 44 a. This solid was used in the next reaction without further purification. The solid was re-dissolved in DMSO (10 mL), Purity (Method A

H. and C. H. , ppm (s, H, NH); 13 C NMR (75 MHz

, ]oxazin-4-yl)propanoyl)-N-phenylpiperazine-1-carboxamide (48): A mixture of 2H-pyrido, vol.2

, ChemMedChem, vol.14, pp.1-19, 2019.

, Weinheim (158 mg, 1.0 mmol), DMF (3 mL, p.3, 2019.

, CDCl 3 ): d = 2.76-2.81 (m, 2 H

H. Hz, ;. Ch-ar, and C. H. Ar, , vol.7

H. , C. H. Ar, ;. , and C. H. Ar, ppm (dd, J = 4.9, 1.5 Hz, 1 H, CH Ar ), vol.13

, Oxoquinoxalin-1(2H)-yl)propanoyl)-N-phenylpiperazine-1-carboxamide (62): A mixture of tert-butyl 3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate 60 (248 mg, 1 mmol, vol.2

, DCC (206 mg, 1 mmol) purified by flash column chromatography (EtOAc/MeOH 10:1) to yield the title compound (102 mg, 25 %). Purity (Method A): 98.86 %. 1 H NMR (300 MHz, The acid was dissolved in DMF (10 mL), and HOBt (153 mg, 1 mmol)

H. , C. H. Ar, ;. , and C. H. Ar, HRMS (ESI): m/z [M + H] + calculated for C 22 H 24 N 5 O 3 406.18737, found 406.1864. 4-(3-(2-Oxobenzo[d]oxazol-3(2H)-yl)propanoyl)-N-phenylpiperazine-1-carboxamide (64): 3-(2-Oxobenzo[d]oxazol-3(2H)-yl)propanoic acid 63 (104 mg, 0.5 mmol) was dissolved in DMF (5 mL) and HOBt (76 mg, 0.5 mmol) and DCC (103 mg, 0.5 mmol) were added at 0 8C. After stirring for 2 h at 0 8C, N-phenylpiperazine-1-carboxamide 16 (102 mg, 0.5 mmol) was added. The mixture was stirred overnight at room temperature. The resulting mixture was diluted with CH 2 Cl 2 (20 mL) and washed with H 2 O (2 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography, p.99

, 4 mmol) and ethyl 3-bromopropionate (380 mg, 2.4 mmol) in DMF (3 mL) was stirred at 80 8C for 48 h. When the reaction was finished, the mixture was diluted with H 2 O (15 mL) and extracted with CH 2 Cl 2 (3 10 mL). The organic phases were combined and washed with H 2 O (15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and evaporated in vacuo. The crude residue was dissolved in THF (5 mL) and a solution of LiOH (42 mg, 1 mmol) in H 2 O (5 mL) was added. The mixture was stirred for 18 h at 60 8C. Then, the solution was adjusted to pH 3 with 2 n HCl and the compound was extracted with EtOAc (3 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After solvent evaporation, the pure acid compound was obtained. The acid was re-dissolved in DMF (5 mL), and HOBt (76 mg, 0.5 mmol) and DCC (103 mg, 0.5 mmol) were added at 0 8C. After stirring for 2 h, N-phenylpiperazine-1-carboxamide 16 (102 mg, 0.5 mmol) was added. The mixture was stirred overnight at room temperature. The resulting mixture was diluted with CH 2 Cl 2 (20 mL) and washed with H 2 O (2 20 mL). The organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography, vol.14, pp.1-19, 2019.

, Weinheim Biological assays, 2019.

, The synthesized compounds were screened using a NADPH oxidation assay for M. tuberculosis ThyX activity in 96-well plates. [27] To determine IC 50 values of compounds 22 g, 27, 28, 29 d, 45 c, 48 and 52, the reaction mixture (100 mL) contained 50 mm HEPES pH7.5, 1 mm MgCl 2 , 12 mm FAD, 0.5 % glycerol, 0.05 % Triton X-100, 0.5 mg mL À1 BSA, Mycobacterial ThyX NADPH oxidase assay: M. tuberculosis ThyX was produced and purified as described

, Global Tuberculosis Report, vol.8, 2017.

L. G. Dover and G. D. Coxon, J. Med. Chem, vol.54, pp.6157-6165, 2011.

K. Andries, P. Verhasselt, J. Guillemont, H. W. Gçhlmann, J. M. Neefs et al., Science, vol.307, pp.223-227, 2005.

M. T. Gler, V. Skripconoka, E. Sanchez-garavito, H. Xiao, J. L. Cabrera-rivero et al., N. Engl. J. Med, vol.366, pp.2151-2160, 2012.

D. T. Hoagland, J. Liu, R. B. Lee, and R. E. Lee, Adv. Drug Deliv. Rev, vol.102, pp.55-72, 2016.

C. W. Carreras and D. V. Santi, Annu. Rev. Biochem, vol.64, pp.721-762, 1995.

H. Myllykallio, G. Lipowski, D. Leduc, J. Filee, P. Forterre et al., Science, vol.297, pp.105-107, 2002.

T. V. Mishanina, L. Yu, K. Karunaratne, D. Mondal, J. M. Corcoran et al., Arch. Biochem. Biophys, vol.2016, pp.96-102, 2010.

I. Mathews, A. M. Deacon, J. M. Canaves, D. Mcmullan, S. A. Lesley et al., Structure, vol.11, pp.677-690, 2003.

A. S. Fivian-hughes, J. Houghton, E. O. Davis-;-b)-j.-rengarajan, B. R. Bloom, and E. J. Rubin, Proc. Natl. Acad. Sci, vol.158, pp.77-84, 2003.

M. Choi, K. Karunaratne, and A. Kohen, Molecules, vol.21, p.654, 2016.

M. Kçgler, B. Vanderhoydonck, S. De-jonghe, J. Rozenski, K. Van-belle et al., J. Med. Chem, vol.54, pp.4847-4862, 2011.

T. Basta, Y. Boum, J. Briffotaux, H. F. Becker, I. Lamarre-jouenne et al., Open Biol, 2012.

S. Skouloubris, K. Djaout, I. Lamarre, J. C. Lambry, K. Anger et al., Open Biol, vol.5, p.150015, 2015.

J. L. Bolton, M. A. Trush, T. M. Penning, G. Dryhurst, and T. J. Monks, Chem. Res. Toxicol, vol.13, pp.135-160, 2000.

F. Esra-Önen, Y. Boum, C. Jacquement, M. V. Spanedda, N. Jaber et al., Bioorg. Med. Chem. Lett, vol.18, pp.3628-3631, 2008.

R. Luciani, P. Saxena, S. Surade, M. Santucci, A. Venturelli et al., J. Med. Chem, vol.59, pp.9269-9275, 2016.

, ChemMedChem, vol.14, pp.1-19, 2019.

R. El-asrar, L. Margamuljana, H. Klaassen, M. Nijs, A. Marchand et al., Biochem. Pharmacol, vol.135, pp.69-78, 2017.

V. Rajachandrashekara, B. G. Vineela, S. Venkataiaha, and P. K. Dubey, Der Pharma Chemica, vol.6, pp.7-10, 2014.

D. S. Johnson, K. Ahn, S. Kesten, S. E. Lazerwith, Y. Song et al., Bioorg. Med. Chem. Lett, vol.19, pp.2865-2869, 2009.

F. L. Atkinson, M. D. Barker, S. A. Campos, N. J. Parr, and V. K. Patel, , 2006.

R. E. Tenbrink, W. B. Im, V. H. Sethy, A. H. Tang, and D. B. Carter, J. Med. Chem, vol.37, pp.758-768, 1994.

E. M. Koehn, L. L. Perissinotti, S. Moghram, A. Prabhakar, S. A. Lesley et al., Proc. Natl. Acad. Sci, vol.109, pp.15722-15727, 2012.

P. Sampathkumar, S. Turley, J. E. Ulmer, H. G. Rhie, C. H. Sibley et al., J. Mol. Biol, vol.352, pp.1091-1104, 2005.

D. A. Case, D. S. Cerutti, T. E. Cheatham, I. , T. A. Darden et al., , 2017.

A. Marchler-bauer, Y. Bo, L. Han, J. He, C. J. Lanczycki et al., Nucleic Acids Res, vol.45, pp.200-203, 2017.

K. Djaout, V. Singh, Y. Boum, V. Katawera, H. F. Becker et al., S. Ekins, Sci. Rep, vol.6, p.27792, 2016.

D. R. Roe, T. E. Cheatham, and I. , J. Chem. Theory Comput, vol.9, pp.3084-3095, 2013.

, Accepted manuscript online, p.0, 2019.

, ChemMedChem, vol.14, pp.1-19, 2019.

-. Wiley, &. Gmbh, . Co, . Kgaa, F. Weinheim et al., (4H)-one analogue with an IC 50 value of 0.69 mm. These heterocycles can be used as starting points for the discovery of novel antibacterial agents that act via ThyX inhibition, Lescrinier* && -&& Synthesis and Structure-Activity Relationship Studies of Benzo, vol.14, pp.1-19, 2019.