Bengamides display potent activity against drug-resistant Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield samples with exceptionally potent activity against M. tuberculosis. Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis. The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania-derived bengamide B was non-toxic against human cell lines, synergised with rifampicin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis. Thus, bengamides isolated from Tedania sp. show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis.

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria

“…Following these pioneering studies of Yu et al, as part of a research programme directed towards the identification of new leads against M. tuberculosis, 1434 diverse marine extracts were screened for their ability to inhibit M. tuberculosis growth in vitro [65]. From this extensive screening, 18 extracts, 11 from the Porifera phylum and 5 from the Chordata phylum, were identified with the ability to inhibit the growth of M. tuberculosis in a 50-0.39 µg/mL range for MIC 50 , defined as the concentration that resulted in 50% survival of bacteria in comparison to untreated controls.…”

Identification of Antimycobacterial Natural Products from a Library of Marine Invertebrate Extracts

“…The 54 active extracts were from marine invertebrate samples, collected from the territorial waters of Mauritius (Indian Ocean) (2), South Africa (Indian and South Atlantic Oceans) (17), Tanzania (Indian Ocean) (8), Palau Island (Pacific Ocean) (4), and Papua-New Guinea (Pacific Ocean) (23). The invertebrates are of the phyla Porifera (46), Cnidaria (2), Chordata (4) and Mollusca (2).…”

“…Synthetic MetAP inhibitors, based on the bengamide structural scaffold, have been described with activity against the Mtb MetAPs (the bacillus encodes two isoforms, MetAP1a and MetAP1c); however, the antimycobacterial potential (whole-cell or target-based) of natural bengamides is less explored [28,29]. There is a report of antimycobacterial activity of bengamide B 9, which exhibited strong in vitro activity against whole-cell Mtb and the purified Mtb MetAP1C protein and was also non-toxic against human cell lines [17]. To our knowledge, ours is the first report of antimycobacterial activity for the second type of bengamides with lipid chains, namely bengamides P 2 and Q 3.…”

“…Anti-mycobacterial activity in the extract from Hyrtios reticulatus was found to be associated with heteronemin 1, while, as expected [15], the extract from Jaspis splendens produced the bengamide class of compounds (see Figure 1), with antitubercular activity shown, for the first time, to be associated with bengamides P and Q (Figure 1, compounds 2 and 3), as well as other inseparable mixtures of bengamides. While other marine-derived and synthetically modified bengamides have previously been shown to be potent antitubercular agents and investigated as drug leads [16,17], to the best of our knowledge, this is the first report of antitubercular activity for bengamides P 2 and Q 3.…”

Bengamide Analogues Show A Potent Antitumor Activity against Colon Cancer Cells: A Preliminary Study

“…This inhibition activity has been recently associated to the antiviral activity against HIV-1 observed by bengamide A [24]. On the other hand, the ability of the bengamides to inhibit MetAPs from Mycobacterium tuberculosis has been exploited in the treatment of tuberculosis [25,26]. These striking biological activities, together with their unique molecular structures, have prompted an intense synthetic activity directed towards the total syntheses of the natural products and analogues thereof analogues in order to identify and develop new chemical entities with improved antitumor and pharmacokinetic properties with respect to the natural counterparts [14,27].…”