Marine Natural Products as Antituberculosis Agents Khalid A. El Sayed, Piotr Bartyzel, Xiaoyu Shen, Tony L. Perry, Jordan K. Zjawiony and Mark T. Hamann * Department of Pharmacognosy, NCNPR School of Pharmacy, The University of Mississippi, MS 38677, USA Received 21 October 1999; revised 28 November 1999; accepted 7 December 1999 Abstract —In an attempt to characterize additional structural classes that could serve as lead antituberculosis agents, 48 structurally diverse marine-derived natural and semisynthetic compounds were examined for in vitro activity against Mycobacterium tuberculosis. Three new classes of compounds including C-19 hydroxy steroids, scalarin sesquiterpenoids and tetrabromo spirocyclohexadienylisoxazolines have been identified as having potential as leads for continued investigations as new antituberculosis agents. New additions to the established antituberculosis structural classes quinone-methide and peptide are also reported.  2000 Elsevier Science Ltd. All rights reserved. Tuberculosis (TB) is a vicious disease that has infected man since the earliest of times and currently infects about 15 million Americans of the two billion people carrying the disease worldwide. 1,2 Although a vaccine (BCG) and effective chemotherapy against TB were available 50 years ago, TB was declared a global emergency in 1993. 3 Over the past 10 years, the area of tuberculosis therapy has undergone a basic change in emphasis for drug therapy. The increase of tuberculosis coinciding with the AIDS epidemic has resulted in additional drug-resistant isolates of Mycobacterium tuberculosis. 4,5 HIV infection has increased the incidence of tuberculosis by causing immuno- suppression, which enables latent infection to clinically progress. 6 The risk of developing tuberculosis among AIDS patients is over 100 times higher than among normal individuals. 7 Tuberculosis is a unique serious disease in that unlike other diseases associated with AIDS, it may be spread by airborne transmission to adults and children who are not at risk of AIDS. 7,8 During 1992, worldwide tuberculosis mortality was two million, with the report of eight million additional new cases. In 1999, 90 million new cases and 30 million deaths from tuberculosis worldwide are expected despite the availa- bility of powerful drugs with activity against the causative pathogen, M. tuberculosis. 9–11 Resistance to the current antituberculosis therapy is another threatening problem. Multi-drug-resistant strains of M. tuberculosis, resistant to as many as nine drugs, are 50–80% fatal even with intensive treatment. In the U.S., drug-resistant strains have been iden- tified in 17 states since 1989. 12 Isoniazid resistance in the U.S. is present in 5.3% and secondary resistance in 19.4% of isolates while the figures for rifampin are 0.6 and 3.2%, respectively. 5,13 The resurgence of drug-resistant-tubercu- losis has generated a renewal of interest in a strategic search for prototype leads. The oceans, with their unique and wide range of biodiversity, producing unusual metabolites, emerges as a good candidate for new antituberculosis agents. In this paper we report the antituberculosis activity for our small library of chemically diverse marine-derived metabolites. Marine-Derived Antimycobacterium Compounds To date, there are only two reports of in vitro anti-TB activ- ity from marine origin. Massetolide A (1) and viscosin (2) are cyclic depsipeptides isolated from cultures of two Pseudomonas species isolated from a marine alga and tube worm, respectively. 14 When tested against M. tuberculosis, massetolide A and viscosin displayed MIC values of 5–10 and 10–20 mg/mL, respectively. When tested against M. avium-intracellulare, massetolide A (1) and viscosin (2) had MICs of 2.5–5 and 5–10 mg/mL, respectively. 14 Pseudopteroxazole (3) and seco-pseudopteroxazole (4) are new benzoxazole diterpene alkaloids isolated from the West Indian gorgonian Pseudopterogorgia elisabethae. 15 Both compounds induced 97 and 66%, respectively, growth inhibition for M. tuberculosis H37Rv at a concentration of 12.5 mg/mL without significant cytotoxicity. 15 These reports illustrate the significance of examining marine- derived secondary metabolites, as a possible unexplored resource for new antimycobacterial leads. Tetrahedron 56 (2000) 949–953 Pergamon TETRAHEDRON 0040–4020/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(99)01093-5 Keywords: antibiotics; natural products; marine metabolites; biologically active compounds. * Corresponding author. Fax: +1-662-915-7026; e-mail: pghamann@cotton.vislab.olemiss.edu