1887

Abstract

Carbon monoxide-releasing molecules (CORMs) are a promising class of new antimicrobials, with multiple modes of action that are distinct from those of standard antibiotics. The relentless increase in antimicrobial resistance, exacerbated by a lack of new antibiotics, necessitates a better understanding of how such novel agents act and might be used synergistically with established antibiotics. This work aimed to understand the mechanism(s) underlying synergy between a manganese-based photoactivated carbon monoxide-releasing molecule (PhotoCORM), [Mn(CO)3(tpa-κ N)]Br [tpa=tris(2-pyridylmethyl)amine], and various classes of antibiotics in their activities towards Escherichia coli EC958, a multi-drug-resistant uropathogen. The title compound acts synergistically with polymyxins [polymyxin B and colistin (polymyxin E)] by damaging the bacterial cytoplasmic membrane. [Mn(CO)3(tpa-κ N)]Br also potentiates the action of doxycycline, resulting in reduced expression of tetA, which encodes a tetracycline efflux pump. We show that, like tetracyclines, the breakdown products of [Mn(CO)3(tpa-κ N)]Br activation chelate iron and trigger an iron starvation response, which we propose to be a further basis for the synergies observed. Conversely, media supplemented with excess iron abrogated the inhibition of growth by doxycycline and the title compound. In conclusion, multiple factors contribute to the ability of this PhotoCORM to increase the efficacy of antibiotics in the polymyxin and tetracycline families. We propose that light-activated carbon monoxide release is not the sole basis of the antimicrobial activities of [Mn(CO)3(tpa-κ N)]Br.

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2017-09-28
2019-10-21
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References

  1. Motterlini R, Mann BE, Foresti R. Therapeutic applications of carbon monoxide-releasing molecules. Expert Opin Investig Drugs 2005; 14: 1305– 1318 [CrossRef] [PubMed]
    [Google Scholar]
  2. Mann BE. Carbon monoxide: an essential signalling molecule. Topics in Organometallic Chemistry 2010; 32: 247– 285 [Crossref]
    [Google Scholar]
  3. Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov 2010; 9: 728– 743 [CrossRef] [PubMed]
    [Google Scholar]
  4. Schatzschneider U. Novel lead structures and activation mechanisms for CO-releasing molecules (CORMs). Br J Pharmacol 2015; 172: 1638– 1650 [CrossRef] [PubMed]
    [Google Scholar]
  5. Hasegawa U, Van der Vlies AJ, Simeoni E, Wandrey C, Hubbell JA. Carbon monoxide-releasing micelles for immunotherapy. J Am Chem Soc 2010; 132: 18273– 18280 [CrossRef] [PubMed]
    [Google Scholar]
  6. Gläser S, Mede R, Görls H, Seupel S, Bohlender C et al. Remote-controlled delivery of CO via photoactive CO-releasing materials on a fiber optical device. Dalton Trans 2016; 45: 13222– 13233 [CrossRef] [PubMed]
    [Google Scholar]
  7. Carmona FJ, Rojas S, Sánchez P, Jeremias H, Marques AR et al. Cation Exchange strategy for the encapsulation of a photoactive CO-releasing organometallic molecule into anionic porous frameworks. Inorg Chem 2016; 55: 6525– 6531 [CrossRef] [PubMed]
    [Google Scholar]
  8. Warburg O. Heavy Metal Prosthetic Groups and Enzyme Action Clarendon Press: Oxford; 1949
    [Google Scholar]
  9. Nobre LS, Seixas JD, Romão CC, Saraiva LM. Antimicrobial action of carbon monoxide-releasing compounds. Antimicrob Agents Chemother 2007; 51: 4303– 4307 [CrossRef] [PubMed]
    [Google Scholar]
  10. Davidge KS, Sanguinetti G, Yee CH, Cox AG, Mcleod CW et al. Carbon monoxide-releasing antibacterial molecules target respiration and global transcriptional regulators. J Biol Chem 2009; 284: 4516– 4524 [CrossRef] [PubMed]
    [Google Scholar]
  11. Jesse HE, Nye TL, Mclean S, Green J, Mann BE et al. The terminal oxidase cytochrome bd-I in Escherichia coli has lower susceptibility than cytochromes bd-II or bo' to inhibition by the carbon monoxide-releasing molecule, CORM-3: N-acetylcysteine reduces CO-RM uptake and inhibition of respiration. Biochim Biophys Acta 1834; 2013: 1693– 1703
    [Google Scholar]
  12. Wilson JL, Jesse HE, Hughes B, Lund V, Naylor K et al. Ru(CO)3Cl(Glycinate) (CORM-3): a carbon monoxide–releasing molecule with broad-spectrum antimicrobial and photosensitive activities against respiration and cation transport in Escherichia coli. Antioxid Redox Signal 2013; 19: 497– 509 [CrossRef] [PubMed]
    [Google Scholar]
  13. Desmard M, Foresti R, Morin D, Dagouassat M, Berdeaux A et al. Differential antibacterial activity against Pseudomonas aeruginosa by carbon monoxide-releasing molecules. Antioxid Redox Signal 2012; 16: 153– 163 [CrossRef] [PubMed]
    [Google Scholar]
  14. Desmard M, Davidge KS, Bouvet O, Morin D, Roux D et al. A carbon monoxide-releasing molecule (CORM-3) exerts bactericidal activity against Pseudomonas aeruginosa and improves survival in an animal model of bacteraemia. FASEB J 2009; 23: 1023– 1031 [CrossRef] [PubMed]
    [Google Scholar]
  15. Southam HM, Butler JA, Chapman JA, Poole RK. The microbiology of ruthenium complexes. In Poole RK. (editor) Advances in Microbial Physiologyvol. 71 London: Elsevier; 2017; pp. 1– 96
    [Google Scholar]
  16. Wareham LK, Poole RK, Tinajero-Trejo M. CO-releasing metal carbonyl compounds as antimicrobial agents in the post-antibiotic era. J Biol Chem 2015; 290: 18999– 19007 [CrossRef] [PubMed]
    [Google Scholar]
  17. Nobre LS, Al-Shahrour F, Dopazo J, Saraiva LM. Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli. Microbiology 2009; 155: 813– 824 [CrossRef] [PubMed]
    [Google Scholar]
  18. Mclean S, Begg R, Jesse HE, Mann BE, Sanguinetti G et al. Analysis of the bacterial response to Ru(CO)3Cl(glycinate) (CORM-3) and the inactivated compound identifies the role played by the ruthenium compound and reveals sulfur-containing species as a major target of CORM-3 action. Antioxid Redox Signal 2013; 19: 1999– 2012 [CrossRef] [PubMed]
    [Google Scholar]
  19. Wilson JL, Wareham LK, Mclean S, Begg R, Greaves S et al. CO-releasing molecules have nonheme targets in bacteria: transcriptomic, mathematical modeling and biochemical analyses of CORM-3 [Ru(CO)3Cl(glycinate)] actions on a heme-deficient mutant of Escherichia coli. Antioxid Redox Signal 2015; 23: 148– 162 [CrossRef] [PubMed]
    [Google Scholar]
  20. Nagel C, Mclean S, Poole RK, Braunschweig H, Kramer T et al. Introducing [Mn(CO)3(tpa-κ3N)]+ as a novel photoactivatable CO-releasing molecule with well-defined iCORM intermediates – synthesis, spectroscopy, and antibacterial activity. Dalton Trans 2014; 43: 9986– 9997 [CrossRef] [PubMed]
    [Google Scholar]
  21. Rimmer RD, Pierri AE, Ford PC. Photochemically activated carbon monoxide release for biological targets. Toward developing air-stable photoCORMs labilized by visible light. Coord Chem Rev 2012; 256: 1509– 1519 [CrossRef]
    [Google Scholar]
  22. Schatzschneider U. PhotoCORMs: Light-triggered release of carbon monoxide from the coordination sphere of transition metal complexes for biological applications. Inorg Chim Acta 2011; 374: 19– 23 [CrossRef]
    [Google Scholar]
  23. Farrer NJ, Salassa L, Sadler PJ. Photoactivated chemotherapy (PACT): the potential of excited-state d-block metals in medicine. Dalton Trans 2009; 10690– 10701 [CrossRef] [PubMed]
    [Google Scholar]
  24. Karakullukcu B, Van Veen RL, Aans JB, Hamming-Vrieze O, Navran A et al. MR and CT based treatment planning for mTHPC mediated interstitial photodynamic therapy of head and neck cancer: description of the method. Lasers Surg Med 2013; 45: n/a– 523 [CrossRef] [PubMed]
    [Google Scholar]
  25. Tinajero-Trejo M, Rana N, Nagel C, Jesse HE, Smith TW et al. Antimicrobial activity of the manganese photoactivated carbon monoxide-releasing molecule [Mn(CO)3(tpa-κ3 N)]+ against a pathogenic Escherichia coli that causes urinary infections. Antiox Redox Signal 2016; 24: 765– 780 [Crossref]
    [Google Scholar]
  26. Totsika M, Beatson SA, Sarkar S, Phan MD, Petty NK et al. Insights into a multidrug resistant Escherichia coli pathogen of the globally disseminated ST131 lineage: genome analysis and virulence mechanisms. PLoS One 2011; 6: e26578 [CrossRef] [PubMed]
    [Google Scholar]
  27. Justice SS, Hung C, Theriot JA, Fletcher DA, Anderson GG et al. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci USA 2004; 101: 1333– 1338 [CrossRef] [PubMed]
    [Google Scholar]
  28. Cantón R, Coque TM. The CTX-M β-lactamase pandemic. Curr Opin Microbiol 2006; 9: 466– 475 [CrossRef] [PubMed]
    [Google Scholar]
  29. Wright KJ, Seed PC, Hultgren SJ. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell Microbiol 2007; 9: 2230– 2241 [CrossRef] [PubMed]
    [Google Scholar]
  30. Hannan TJ, Totsika M, Mansfield KJ, Moore KH, Schembri MA et al. Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev 2012; 36: 616– 648 [CrossRef] [PubMed]
    [Google Scholar]
  31. Nightingale CH, Ambrose PG, Drusano GL, Murakawa T. (editors) Antimicrobial Pharmacodynamics in Theory and Clinical Practice, 2nd ed. (Infectious Disease and Therapy) New York, London: Informa Healthcare; 2007; [Crossref]
    [Google Scholar]
  32. European Committee on Antimicrobial Susceptibility Testing E 2017; Clinical breakpoints. Accessed www.eucast.org/
  33. Flatley J, Barrett J, Pullan ST, Hughes MN, Green J et al. Transcriptional responses of Escherichia coli to S-nitrosoglutathione under defined chemostat conditions reveal major changes in methionine biosynthesis. J Biol Chem 2005; 280: 10065– 10072 [CrossRef] [PubMed]
    [Google Scholar]
  34. Orhan G, Bayram A, Zer Y, Balci I. Synergy tests by E test and checkerboard methods of antimicrobial combinations against Brucella melitensis. J Clin Microbiol 2005; 43: 140– 143 [CrossRef] [PubMed]
    [Google Scholar]
  35. Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 2003; 52: 1 [CrossRef] [PubMed]
    [Google Scholar]
  36. Neidhardt FC, Ingraham JL, Schaechter M. Physiology of the Bacterial Cell: A Molecular Approach Sunderland, Mass, USA: Sinauer Associates, Inc; 1990
    [Google Scholar]
  37. Hashizaki K, Taguchi H, Sakai H, Abe M, Saito Y et al. Carboxyfluorescein leakage from poly(ethylene glycol)-grafted liposomes induced by the interaction with serum. Chem Pharm Bull 2006; 54: 80– 84 [CrossRef] [PubMed]
    [Google Scholar]
  38. Lv Y, Wang J, Gao H, Wang Z, Dong N et al. Antimicrobial properties and membrane-active mechanism of a potential α-helical antimicrobial derived from cathelicidin PMAP-36. PLoS One 2014; 9: e86364 [CrossRef] [PubMed]
    [Google Scholar]
  39. Schwyn B, Neilands JB. Universal chemical assay for the detection and determination of siderophores. Anal Biochem 1987; 160: 47– 56 [CrossRef] [PubMed]
    [Google Scholar]
  40. Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta 2006; 1758: 1408– 1425 [CrossRef] [PubMed]
    [Google Scholar]
  41. Berends H-M, Kurz P. Investigation of light-triggered carbon monoxide release from two manganese photoCORMs by IR, UV–Vis and EPR spectroscopy. Inorganica Chim Acta 2012; 380: 141– 147 [CrossRef]
    [Google Scholar]
  42. Sachs U, Schaper G, Winkler D, Kratzert D, Kurz P. Light- or oxidation-triggered CO release from [MnI(CO)33-L)] complexes: reaction intermediates and a new synthetic route to [MnIII/IV 2(μ-O)2(L)2] compounds. Dalton Trans 2016; 45: 17464– 17473 [CrossRef] [PubMed]
    [Google Scholar]
  43. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001; 65: 232– 260 [CrossRef] [PubMed]
    [Google Scholar]
  44. Little JW, Mount DW. The SOS regulatory system of Escherichia coli. Cell 1982; 29: 11– 22 [CrossRef] [PubMed]
    [Google Scholar]
  45. Tavares AF, Teixeira M, Romão CC, Seixas JD, Nobre LS et al. Reactive oxygen species mediate bactericidal killing elicited by carbon monoxide-releasing molecules. J Biol Chem 2011; 286: 26708– 26717 [CrossRef] [PubMed]
    [Google Scholar]
  46. Tavares AF, Nobre LS, Saraiva LM. A role for reactive oxygen species in the antibacterial properties of carbon monoxide-releasing molecules. FEMS Microbiol Lett 2012; 336: 1– 10 [CrossRef] [PubMed]
    [Google Scholar]
  47. Wareham LK, Begg R, Jesse HE, van Beilen JW, Ali S et al. Carbon monoxide gas is not inert, but global, in its consequences for bacterial gene expression, iron acquisition, and antibiotic resistance. Antioxid Redox Signal 2016; 24: 1013– 1028 [CrossRef] [PubMed]
    [Google Scholar]
  48. Pirt SJ. Principles of Microbe and Cell Cultivation Oxford: Blackwell Scientific Publications; 1985
    [Google Scholar]
  49. Ihnat PM, Vennerstrom JL, Robinson DH. Solution equilibria of deferoxamine amides. J Pharm Sci 2002; 91: 1733– 1741 [CrossRef] [PubMed]
    [Google Scholar]
  50. Miles AA, Maskell JP. The antagonism of tetracycline and ferric iron in vivo. J Med Microbiol 1985; 20: 17– 26 [CrossRef] [PubMed]
    [Google Scholar]
  51. Miles AA, Maskell JP. The neutralization of antibiotic action by metallic cations and iron chelators. J Antimicrob Chemother 1986; 17: 481– 487 [CrossRef] [PubMed]
    [Google Scholar]
  52. Avery AM, Goddard HJ, Sumner ER, Avery SV. Iron blocks the accumulation and activity of tetracyclines in bacteria. Antimicrob Agents Chemother 2004; 48: 1892– 1894 [CrossRef] [PubMed]
    [Google Scholar]
  53. Grenier D, Huot MP, Mayrand D. Iron-chelating activity of tetracyclines and its impact on the susceptibility of Actinobacillus actinomycetemcomitans to these antibiotics. Antimicrob Agents Chemother 2000; 44: 763– 766 [CrossRef] [PubMed]
    [Google Scholar]
  54. Alanis AJ. Resistance to antibiotics: are we in the post-antibiotic era?. Arch Med Res 2005; 36: 697– 705 [CrossRef] [PubMed]
    [Google Scholar]
  55. Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016; 16: 161– 168 [CrossRef] [PubMed]
    [Google Scholar]
  56. Ejim L, Farha MA, Falconer SB, Wildenhain J, Coombes BK et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol 2011; 7: 348– 350 [CrossRef] [PubMed]
    [Google Scholar]
  57. WHO 2017; Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Accessed www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/
  58. Evans ME, Feola DJ, Rapp RP. Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacother 1999; 33: 960– 967 [CrossRef] [PubMed]
    [Google Scholar]
  59. Li J, Turnidge J, Milne R, Nation RL, Coulthard K. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 2001; 45: 781– 785 [CrossRef] [PubMed]
    [Google Scholar]
  60. Pradines B, Ramiandrasoa F, Rolain JM, Rogier C, Mosnier J et al. In vitro potentiation of antibiotic activities by a catecholate iron chelator against chloroquine-resistant Plasmodium falciparum. Antimicrob Agents Chemother 2002; 46: 225– 228 [CrossRef] [PubMed]
    [Google Scholar]
  61. Yep A, Mcquade T, Kirchhoff P, Larsen M, Mobley HL. Inhibitors of TonB function identified by a high-throughput screen for inhibitors of iron acquisition in uropathogenic Escherichia coli CFT073. MBio 2014; 5: e01089-13 [CrossRef] [PubMed]
    [Google Scholar]
  62. Gusarov I, Shatalin K, Starodubtseva M, Nudler E. Endogenous nitric oxide protects bacteria against a wide spectrum of antibiotics. Science 2009; 325: 1380– 1384 [CrossRef] [PubMed]
    [Google Scholar]
  63. Shatalin K, Shatalina E, Mironov A, Nudler E. H2S: a universal defense against antibiotics in bacteria. Science 2011; 334: 986– 990 [CrossRef] [PubMed]
    [Google Scholar]
  64. Tavares AF, Parente MR, Justino MC, Oleastro M, Nobre LS et al. The bactericidal activity of carbon monoxide-releasing molecules against Helicobacter pylori. PLoS One 2013; 8: e83157 [CrossRef] [PubMed]
    [Google Scholar]
  65. Murray TS, Okegbe C, Gao Y, Kazmierczak BI, Motterlini R et al. The carbon monoxide releasing molecule CORM-2 attenuates Pseudomonas aeruginosa biofilm formation. PLoS One 2012; 7: e35499 [CrossRef] [PubMed]
    [Google Scholar]
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