Calpinactam, a new anti-mycobacterial agent, produced by Mortierella alpina FKI-4905

Abstract

Calpinactam, a new anti-mycobacterial agent, was isolated from the culture broth of a fungal strain Mortierella alpina FKI-4905 by solvent extraction, octadecyl silane column chromatography and preparative HPLC. Calpinactam was active only against Mycobacteria among various microorganisms, including Gram-positive and Gram-negative bacteria, fungi and yeasts. Calpinactam inhibited the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis with MIC values of 0.78 and 12.5 lg ml À1 , respectively. The Journal of Antibiotics (2010) 63, 183-186; doi:10.1038/ja.2010.14; published online 26 February 2010Keywords: anti-mycobacterial peptide; calpinactam; fungal metabolite; mycobactin; tuberculosis INTRODUCTIONOur research group has focused on the discovery of anti-infectives from microbial metabolites. 1-5 Tuberculosis (TB) is still the greatest single infectious cause of mortality in the world, together with human immunodeficiency virus and malaria. 6 Moreover, the spread of human immunodeficiency virus has resulted in an increase in the number of TB patients. 7 However, no new anti-TB agents have been developed for over 30 years, and only five anti-TB drugs can be used clinically at present. It is therefore increasingly urgent and necessary to discover anti-TB drugs with a new mechanism of action. As isoniazid and ethambutol, first-line anti-TB drugs, show selective inhibition against Mycobacteria, we have screened for microbial metabolites having selective inhibition against Mycobacterium smegmatis among 14 test microorganisms, including Gram-positive and Gram-negative bacteria, fungi and yeasts. By this screening system, we discovered and reported lariaitins, new lasso polypeptides, from actinomycete Rhodococcus metabolites. [8][9][10] During the continuous screening program, we isolated calpinactam (Figure 1), a new hexapeptide with a caprolactam ring at the C-terminal, from the culture broth of the fungal strain Mortierela alpina FKI-4905 (Figure 2). The structure elucidation of calpinactam is described in detail elsewhere. 11 In this report, the taxonomy of the producing strain, fermentation, isolation and biological properties of calpinactam are described.

Structure-Activity Relationships of Wollamide Cyclic Hexapeptides with Activity against Drug-Resistant and Intracellular Mycobacterium tuberculosis

“…For example, bacterial lassomycin from Lentzea kentuckyensis targets an essential mycobacterial ATP-dependent protease (ClpC1P1P2) (17), sansanmycin from a Streptomyces species inhibits phosphor-MurNAcpentapeptide translocase involved in the synthesis of mycobacterial lipid I (18), and capreomycin from Streptomyces capreolus inhibits L12-L10 to disrupt ribosomal GTPase activity and ribosome-dependent protein synthesis (19,20). Similarly, fungal calpinactam from Mortierella alpine affects mycobacterial cell wall biosynthesis (21,22), while trichoderins from a marine sponge-derived Tricoderma species obstruct mycobacterial ATP synthesis (23). The wollamides are a class of microbial peptides with potent antimycobacterial activity that are of considerable interest due to their low cytotoxicity and synthetic accessibility.…”

Antibacterial activity of long-chain fatty alcohols against mycobacteria

“…The search for antimycobacterial agents for both therapy and disinfection is therefore now of major research interest across the world. In this regard, research describing new antimycobcaterial agents from natural and synthetic sources is being reported with different target sites and mode of actions (Koyama et al ., ; Kakwani et al ., ; Lougheed et al ., ).…”

Anti-Mycobacterium activity of microbial peptides in a silkworm infection model with Mycobacterium smegmatis

“…As a result, lariatins (lasso peptides, Figure 1) and calpinactam (a hexapeptide, Figure 1) were discovered from microorganisms in this assay, and were found to exhibit anti-TB activities in vitro. [11][12][13][14] As the next step, the in vivo efficacies of these microbial peptides need to be tested.…”