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Table 3. Activity of selected compounds against Mycobacterium tuberculosis
Compd
Structurea
MICsb (mg/mL) against M. tuberculosis strainsc
H37Rv
TN913
TN565 (W)
TN1618 (P)
Pacidamycin 4d
m-Tyr
Gly
Ala
Ala
LeuTrp
Met
Trp
>30
>30
>30
30
>30
30
>30
30
>30
10
>30
30
>30
10
>30
10
12
13
14
15
10
16
17
18
19
Tyr
2-NAL
Ala
Phe
LeuPhe
Ala
Ala
Ala
Ala
Trp
30
30
30
10
4-FPA
4-BIP
Phe
4-FPA
4-TFM
Tyr
Trp
Trp
Trp
Trp
10
8
8
8
8
8
4
8
8
4
8
4
4
4
4
10
10
8
8
8
Ala
aRefer to the general structure in Table 1.
bMICs were measured at 3 weeks and were done by increasing drug concentration by 2-fold dilution until 8 mg/mL, the next growth points were then
10 and 30 mg/mL.
cH37Rv and TN913 are susceptible to rifampicin (RIF), isoniazide (INH), ethambutol (EMB), streptomycin (STREP) ethionamide (ETH), kana-
mycin (KAN), capreomycin (CAP), ciprofloxacin (CIP), cycloserine. TN565 (W) is resistant to INH, RIF, KAN, STREP, EMB, ETH, CIP.
TN1618 (P) is resistant to INH, RIF, STREP, EMB, ETH, CIP, CAP, p-aminosalicylic acid.
dThe natural product pacidamycins all have a 30-deoxyuracil with a C(40)–C(50) exocyclic olefin. m-Tyr, meta-tyrosine; 4-FPA, 4-fluoro-
phenylalanine; 2-NAL, (2-naphthyl)alanine; 4-BIP, (4-biphenyl)alanine; 4-TFM, 4-trifluoromethylphenylalanine.
dansylated UDP-MurNAc-pentapeptide substrate in
lipid vesicles containing decaprenol-phosphate.13 They
have shown these synthetic UPA derivatives, like the
natural products, to be potent inhibitors of MraY iso-
lated from E. coli (e.g., IC50 for 10=15 nM). A full
disclosure of enzyme inhibition SAR along with the
experimental details of their assay will be reported in
due course.
J. Soos for his support during the execution of this
work; he will be missed (in memoriam, AD 1986-2002).
References and Notes
1. (a) Brown, P. D.; Lerner, S. A. Lancet 1998, 352, 1295. (b)
Spach, D. H.; Black, D. Ann. Allergy Asthma Immunol. 1998,
81, 293. (c) Bugg, T. D.; Walsh, C. T. Nat. Prod. Rep. 1992, 9,
199. (d) Gold, H. S.; Moellering, R. C., Jr. N. Engl. J. Med.
1996, 335, 1445. (e) Cohen, M. L. Ann. Emerg. Med. 1994, 24,
454. (f) Jacoby, G. A. Annu. Rev. Med. 1996, 47, 169. (g)
Nikaido, H. Science 1994, 264, 382. (h) Puzniak, L. A.; Leet,
T.; Mayfield, J.; Kollef, M.; Mundy, L. M. Clin. Infec. Dis.
2002, 35, 18.
2. (a) Malabarba, A.; Ciabatti, R. Curr. Med. Chem. 2001, 8,
1759. (b) Wu, Y.-J.; Su, W.-G. Curr. Med. Chem. 2001, 8,
1727. Bronson, J. J.; Barrett, J. F. Curr. Med. Chem. 2001, 8,
1775.
3. (a) Lomovskaya, O.; Watkins, W. J. Curr. Med. Chem.
2001, 8, 1699. (b) Renau, T. E.; Leger, R.; Flamme, E. M.;
Sangalang, J.; She, M. W.; Yen, R.; Gannon, C. L.; Griffith,
D.; Chamberland, S.; Lomovskaya, O.; Hecker, S. J.; Lee, V.
J; Ohta, T.; Nakayama, K. J. Med. Chem. 1999, 42, 4928. (c)
Renau, T. E.; Lemoine, R. C. Drugs Future 2001, 26, 1171. (d)
Also note combination products on the market such as the
beta-lactam antibiotic amoxicillin paired with the beta-
lactamase inhibitor clavulanic acid.
For the first time, the spectrum of the UPAs has been
modified to include additional gram negative pathogens
including E. coli (both wild-type and multi-resistant
clinical strains), and organisms of the genus Citrobacter.
Additionally, a synthetic dihydropacidamycin 4-fold
more potent against P. aeruginosa than the natural
product pacidamycin 4 has been identified. The chal-
lenge of finding novel antituberculosis agents is a diffi-
cult one; thus it is striking that three synthetic
dihydropacidamycins have activity in the 4–8 mg/mL
range against both wild-type and multiply resistant
strains, especially since the natural product pacidamycin
4 is shown to be inactive against these organisms.
Acknowledgements
The authors would like to thank Dr. Barry Krieswirth
of the PHRI in NYC for the evaluation of the M.
tuberculosis MICs. The authors are grateful to Olga
Lomoskaya for her scientific input and suggestions as
this work was being carried out. We would also like to
thank Professor Jonathan A. Ellman and Dr. Derek
Cogan for technical assistance and Dr. Will J. Watkins
for helpful discussions. We are also grateful for micro-
biological assistance of Carla (Ford) Gannon, Cynthia
Dinh, and Monica Hoang. Our thanks also go to Fran-
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c¸ ois Malouin, Tien Nguyen, and Samia Hakem for
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validating MraY inhibition as the mechanism of action
of this class of synthetic compounds, and for the IC50
provided for compound 10. Thank youalso to Momar