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Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance



The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.

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Figure 1: AMA inactivates MBLs.
Figure 2: AMA potentiates the activity of meropenem against carbapenem-resistant Gram-negative pathogens.
Figure 3: AMA rescues meropenem activity in vivo.


  1. 1

    Frère, J. M. Beta-Lactamases (Nova Science, 2011)

    Google Scholar 

  2. 2

    Pitout, J. D. & Laupland, K. B. Extended-spectrum β-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect. Dis. 8, 159–166 (2008)

    CAS  Article  Google Scholar 

  3. 3

    Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States (Atlanta, Georgia, 2013)

  4. 4

    Edelstein, M. V. et al. Spread of extensively resistant VIM-2-positive ST235 Pseudomonas aeruginosa in Belarus, Kazakhstan, and Russia: a longitudinal epidemiological and clinical study. Lancet Infect. Dis. 13, 867–876 (2013)

    Article  Google Scholar 

  5. 5

    Patel, G. & Bonomo, R. A. “Stormy waters ahead”: global emergence of carbapenemases. Front. Microbiol. 4, 48 (2013)

    Article  Google Scholar 

  6. 6

    Frias, M. et al. New Delhi metallo-β-lactamase-producing Escherichia coli associated with endoscopic retrograde cholangiopancreatography — Illinois, 2013. MMWR Morb. Mortal. Wkly Rep. 62, 1051 (2014)

    Google Scholar 

  7. 7

    Chang, Y. Laboratory Trends, December 17. 8 (BC Public Health Microbiology & Reference Laboratory, Vancouver, British Columbia, 2013)

  8. 8

    Yigit, H. et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob. Agents Chemother. 45, 1151–1161 (2001)

    CAS  Article  Google Scholar 

  9. 9

    Bush, K. Proliferation and significance of clinically relevant β-lactamases. Ann. NY Acad. Sci. 1277, 84–90 (2013)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Drawz, S. M. & Bonomo, R. A. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 23, 160–201 (2010)

    CAS  Article  Google Scholar 

  11. 11

    Fast, W. & Sutton, L. D. Metallo-β-lactamase: inhibitors and reporter substrates. Biochim. Biophys. Acta 1834, 1648–1659 (2013)

    CAS  Article  Google Scholar 

  12. 12

    Buynak, J. D. β-Lactamase inhibitors: a review of the patent literature (2010–2013). Expert Opin. Ther. Pat. 23, 1469–1481 (2013)

    CAS  Article  Google Scholar 

  13. 13

    Ricci, D. P. & Silhavy, T. J. The Bam machine: a molecular cooper. Biochim. Biophys. Acta 1818, 1067–1084 (2012)

    CAS  Article  Google Scholar 

  14. 14

    Blair, J. M. & Piddock, L. J. Structure, function and inhibition of RND efflux pumps in Gram-negative bacteria: an update. Curr. Opin. Microbiol. 12, 512–519 (2009)

    CAS  Article  Google Scholar 

  15. 15

    Haenni, A. L. et al. Structure chimique des aspergillomarasmines A et B. Helv. Chim. Acta 48, 729–750 (1965)

    CAS  Article  Google Scholar 

  16. 16

    Mikami, Y. & Suzuki, T. Novel microbial inhibitors of angiotensin-converting enzyme, aspergillomarasmines A and B. Agric. Biol. Chem. 47, 2693–2695 (1983)

    CAS  Google Scholar 

  17. 17

    Arai, K. et al. Aspergillomarasmine A and B, potent microbial inhibitors of endothelin-converting enzyme. Biosci. Biotechnol. Biochem. 57, 1944–1945 (1993)

    CAS  Article  Google Scholar 

  18. 18

    Matsuura, A. et al. Pharmacological profiles of aspergillomarasmines as endothelin converting enzyme inhibitors. Jpn. J. Pharmacol. 63, 187–193 (1993)

    CAS  Article  Google Scholar 

  19. 19

    Hernandez Valladares, M. et al. Zn(II) dependence of the Aeromonas hydrophila AE036 metallo-β-lactamase activity and stability. Biochemistry 36, 11534–11541 (1997)

    CAS  Article  Google Scholar 

  20. 20

    Docquier, J. D. et al. On functional and structural heterogeneity of VIM-type metallo-beta-lactamases. J. Antimicrob. Chemother. 51, 257–266 (2003)

    CAS  Article  Google Scholar 

  21. 21

    Pillai, S. K., Moellering, R. C., Jr & Eliopoulos, G. M. in Antibiotics in Laboratory Medicine (ed. V. Lorian ) 365–440 (Williams & Wilkins, 2005)

    Google Scholar 

  22. 22

    Shlaes, D. M. New β-lactam-β-lactamase inhibitor combinations in clinical development. Ann. NY Acad. Sci. 1277, 105–114 (2013)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Holmquist, B., Bunning, P. & Riordan, J. F. A continuous spectrophotometric assay for angiotensin converting enzyme. Anal. Biochem. 95, 540–548 (1979)

    CAS  Article  Google Scholar 

  24. 24

    Lee, M., Hesek, D. & Mobashery, S. A practical synthesis of nitrocefin. J. Org. Chem. 70, 367–369 (2005)

    CAS  Article  Google Scholar 

  25. 25

    Petersen, T. N., Brunak, S., von Heijne, G. & Nielsen, H. SignalP 4.0: discriminating signal peptides from transmembrane regions. Nature Methods 8, 785–786 (2011)

    CAS  Article  Google Scholar 

  26. 26

    Zhang, J. H., Chung, T. D. & Oldenburg, K. R. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J. Biomol. Screen. 4, 67–73 (1999)

    CAS  Article  Google Scholar 

  27. 27

    King, D. T., Worrall, L. J., Gruninger, R. & Strynadka, N. C. New Delhi metallo-β-lactamase: structural insights into β-lactam recognition and inhibition. J. Am. Chem. Soc. 134, 11362–11365 (2012)

    CAS  Article  Google Scholar 

  28. 28

    EUCAST. Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0. (2014)

  29. 29

    Marra, A. et al. Effect of linezolid on the 50% lethal dose and 50% protective dose in treatment of infections by Gram-negative pathogens in naive and immunosuppressed mice and on the efficacy of ciprofloxacin in an acute murine model of septicemia. Antimicrob. Agents Chemother. 56, 4671–4675 (2012)

    CAS  Article  Google Scholar 

  30. 30

    Endimiani, A. et al. Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrob. Agents Chemother. 55, 82–85 (2011

    CAS  Article  Google Scholar 

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We thank M. Mulvey (Public Health Agency of Canada) and R. Melano (Public Health Ontario) for clinical strains. We thank L. Rossi for her work in constructing the screening strain. AMA inhibition activity on clinical strains by T.R.W. was funded by the UK Medical Research Council (G1100135). This research was funded by a Canadian Institutes of Health Research Grant (MT-13536), Natural Sciences and Engineering Research Council Grant (237480), and by a Canada Research Chair in Infectious Disease Pathogenesis (to B.K.C.) and Antibiotic Biochemistry (to G.D.W.).

Author information




A.M.K., G.D.W., S.A.R.-Y., B.K.C., T.R.W. and N.C.S. designed experiments; G.D.P. and A.M.K. designed and engineered the E. coli strains and screened extracts; A.M.K. synthesized nitrocefin; A.M.K. cloned constructs; A.M.K. and D.T.K. purified enzymes; A.M.K. performed enzyme kinetics; W.W. and A.M.K. fermented WAC-138 and purified AMA; W.W. elucidated AMA structure; A.M.K. performed FIC experiments; D.T.K. performed ICP-MS; S.A.R.-Y. and B.K.C. designed the animal studies; S.A.R.-Y. and A.M.K. performed animal experiments; T.R.W. performed the clinical isolate screen; and A.M.K. and G.D.W. principally wrote the manuscript with input from all.

Corresponding author

Correspondence to Gerard D. Wright.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 1H NMR spectrum of AMA in D2O.

Extended Data Figure 2 13C NMR spectrum of AMA in D2O.

Extended Data Figure 3 1H-1H COSY NMR spectrum of AMA in D2O.

Extended Data Figure 4 1H-13C HSQC NMR spectrum of AMA in D2O.

Extended Data Figure 5 1H-13C HMBC NMR spectrum of AMA in D2O.

Extended Data Figure 6 IC50 inhibition profiles for select SBLs and ACE.

a, b, Experiments were done as in Fig. 1b for ACE and CTX-M-15 (black circles), KPC-2 (white circles), and TEM-1 (black squares). Error bars denote standard deviation of at least two replicates.

Extended Data Figure 7 Effects of meropenem dosage on spleen burden.

CD-1 mice were infected with K. pneumoniae N11-2218 by i.p. injection. Mice were treated with either PBS (n = 6) or various doses of meropenem (n = 3 per group) by s.c. injection. Mice were euthanized 48 h after infection, and the bacterial load in the spleen was determined by selective plating. Data are the means with standard error.

Extended Data Table 1 1H and 13C NMR Data of aspergillomarasmine in D2O
Extended Data Table 2 Per cent residual activity following metalloenzyme incubation with AMA
Extended Data Table 3 FIC indices against select clinical isolates of CRE

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King, A., Reid-Yu, S., Wang, W. et al. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature 510, 503–506 (2014).

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