Antimycobacterial activity of cerulenin and its effects on lipid biosynthesis

Parrish, Nikki; Kuhajda, Francis P.; Heine, Henry S.; Bishai, William R.; Dick, James D.

doi:10.1093/jac/43.2.219

Cited by 42 publications

(39 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Taken together, these results show that M. tuberculosis is more susceptible to 5-Cl-PZA than M. smegmatis. Furthermore, the MICs of cerulenin, a FASI (and possibly FASII) inhibitor (22), and isoniazid, a FASII inhibitor (1,29,30) Table 2 and Fig. 2.…”

Section: Construction Of MCmentioning

confidence: 99%

“…The FASII enoyl-ACP reductase was identified as the target of isoniazid and ethionamide, which are first-and second-line tuberculosis drugs (1), as well as a universal bacterial target for triclosan, a consumer antimicrobial agent (13,(18)(19)(20)(21)28). The fungal metabolites cerulenin and thiolactomycin target the condensing enzymes of the bacterial FASII pathway (10,17,22,24,25). Two studies have shown that 5-chloro-pyrazinamide (5-Cl-PZA) (5, 32) and pyrazinamide (PZA) (32) inhibit M. tuberculosis FASI, indicating that FASI is also a drug target.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Mycobacterium smegmatis Expressing the Mycobacterium tuberculosis Fatty Acid Synthase I ( fas1 ) Gene

2004

View full text Add to dashboard Cite

Unlike most other bacteria, mycobacteria make fatty acids with the multidomain enzyme eukaryote-like fatty acid synthase I (FASI). Previous studies have demonstrated that the tuberculosis drug pyrazinamide and 5-chloro-pyrazinamide target FASI activity. Biochemical studies have revealed that in addition to C 16:0 , Mycobacterium tuberculosis FASI synthesizes C 26:0 fatty acid, while the Mycobacterium smegmatis enzyme makes C 24:0 fatty acid. In order to express M. tuberculosis FASI in a rapidly growing Mycobacterium and to characterize the M. tuberculosis FASI in vivo, we constructed an M. smegmatis ⌬fas1 strain which contained the M. tuberculosis fas1 homologue. The M. smegmatis ⌬fas1 (attB::M. tuberculosis fas1) strain grew more slowly than the parental M. smegmatis strain and was more susceptible to 5-chloro-pyrazinamide. Surprisingly, while the M. smegmatis ⌬fas1 (attB::M. tuberculosis fas1) strain produced C 26:0 , it predominantly produced C 24:0 . These results suggest that the fatty acid elongation that produces C 24:0 or C 26:0 in vivo is due to a complex interaction among FASI, FabH, and FASII and possibly other systems and is not solely due to FASI elongation, as previously suggested by in vitro studies.Mycobacterium tuberculosis infects one-third of the world's population, and it is estimated that 1% of the world's population is newly infected with this organism each year (31). The mycobacterial cell wall is a complex structure that plays a role in both M. tuberculosis virulence and drug resistance (12, 16). These features of the mycobacterial cell wall are conferred by a wide variety of unique lipids that compose 60% of the cell wall. Mycolic acids (C 74 to C 90 ␣-alkyl ␤-hydroxyl fatty acids) are the major lipid components of the mycobacterial cell wall and the hallmark of mycobacteria and related species (16). Long-chain saturated fatty acids, which are precursors of cell membrane phospholipids, mycolic acids, and other complex lipids, are generated by the type I fatty acid synthase (FASI) in mycobacteria (4,6,16). Mycobacteria are unusual among prokaryotes in that they possess both FASI (typically found in parasites, fungi, and all higher eukaryotes) and the type II fatty acid synthase (FASII), which is found in most prokaryotes and plants. The multifunctional FASI enzyme is a monomer that contains seven separate domains with catalytic activities, including an active site for the prosthetic group 4Ј-phosphopantetheine of the acyl carrier protein (ACP) (4, 6). Mycobacterial FASI generates C 16:0 from acetyl coenzyme A (acetylCoA) primers and elongates the molecules to produce C 24:0/26:0 fatty acyl-CoA derivatives, which are the precursors of other fatty acid synthases and polyketide systems (8,16). In contrast, FASII elongates the FASI products to produce meromycolate precursors, which are modified and condensed with C 24:0/26:0 to form mycolic acids (8,16). In vitro studies have shown that mycobacterial FASI produces a unique bimodal distribution of fatty acids (15,23). In addition to C 16:0 , C...

show abstract

Section: Construction Of MCmentioning

confidence: 99%

mentioning

confidence: 99%

Characterization of Mycobacterium smegmatis Expressing the Mycobacterium tuberculosis Fatty Acid Synthase I ( fas1 ) Gene

2004

View full text Add to dashboard Cite

show abstract

“…The combination of vancomycin and cerulenin, a potent long-chain lipid synthesis inhibitor (23,24), was used at a sub-MIC on M. tuberculosis H37Rv and on MDR and XDR M. tuberculosis clinical isolates. Thirteen clinically unrelated isolates were selected from a M. tuberculosis collection (Tuberculosis Center, Public Health Research Institute [PHRI], NJ) (25).…”

mentioning

confidence: 99%

Increased Vancomycin Susceptibility in Mycobacteria: a New Approach To Identify Synergistic Activity against Multidrug-Resistant Mycobacteria

Soetaert

Rens

Wang

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Mycobacterium tuberculosis is wrapped in complex waxes, impermeable to most antibiotics. Comparing Mycobacterium bovis BCG and M. tuberculosis mutants that lack phthiocerol dimycocerosates (PDIM) and/or phenolic glycolipids with wild-type strains, we observed that glycopeptides strongly inhibited PDIM-deprived mycobacteria. Vancomycin together with a drug targeting lipid synthesis inhibited multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical isolates. Our study puts glycopeptides in the pipeline of potential antituberculosis (TB) agents and might provide a new antimycobacterial drugscreening strategy. Mycobacterium tuberculosis remains a leading cause of morbidity, tuberculosis (TB), and mortality in the world. M. tuberculosis is intrinsically resistant to most classical antibiotics, partly because of its impermeable cell wall (1-6). Due to selective mutations in M. tuberculosis, almost one-third of new TB patients are now infected with first-line drug-resistant strains, monoresistant strains, or multidrug-resistant (MDR) strains. Consequently, second-line therapies are often implemented, leading to the appearance of extensively drug-resistant (XDR) strains (7,8). There is therefore a growing urgency in the need for new antimycobacterial therapies.The mycobacterial cell wall is composed of peptidoglycan covalently attached to arabinogalactan, which are in turn esterified by very-long-chain mycolic acids. Various noncovalently attached lipids are embedded at the outer surface and necessary for capsule formation. Among these lipids, two related waxes, phthiocerol dimycocerosates (PDIM) and phenolic glycolipids (PGL), are involved in virulence (9-11). PDIM and PGL are only or mostly, respectively, found in pathogenic mycobacteria, but their roles in antibiotic resistance remain unclear (12-16). In Mycobacterium marinum, a mild (2-to 10-fold) increase in antibiotic susceptibility was observed in PDIM-and PGL-deficient strains (14, 15). In contrast, in PDIM-and PGL-deficient M. tuberculosis, no change was detected (13).The present study aimed to understand how mycobacteria can become susceptible to glycopeptides. Using PDIM-negative and/or PGL-negative strains of Mycobacterium bovis BCG and M. tuberculosis, we investigated the correlation between the absence of PDIM and the glycopeptide susceptibility. Subsequently, we investigated whether vancomycin could synergistically inhibit MDR and XDR strains with a mycobacterial lipids synthesis inhibitor.We recently reported that the chaperonin Cpn60.1/GroEL-1/ Hsp60-1 of M. bovis BCG was necessary for the integrity of the cell wall as the ⌬cpn60.1 strain showed an abnormal mycobacterial cell wall with a lack of PDIM and mycolates with two more carbon atoms (17). We investigated the susceptibility of the wild-type (WT), ⌬cpn60.1, and complemented ⌬cpn60.1 M. bovis BCG (GL2 strain) strains to several antituberculosis drugs. We used the NCCLS agar proportion method (18) to determine the MIC scale range of each antibiotic. We inoculated equal quantities of s...

show abstract

“…In the past, characterization of FAS has been aided through the use of two natural product inhibitors of FAS components, cerulenin and thiolactomycin (15,16,36,(39)(40)(41)(42)46). Cerulenin is a potent inhibitor of both FAS I and FAS II systems while thiolactomycin inhibits only synthases of the FAS II variety.…”

mentioning

confidence: 99%

“…Cerulenin is a potent inhibitor of both FAS I and FAS II systems while thiolactomycin inhibits only synthases of the FAS II variety. Activity of both of these inhibitors on the mycolic acids of mycobacteria has recently been described (25,42,50). Although cerulenin and thiolactomycin are structurally different, both compounds inhibit the two-carbon homologation catalyzed by the ␤-ketoacyl synthase, the condensing enzyme required for fatty acid biosynthesis.…”

mentioning

confidence: 99%

In Vitro Activity of a Novel Antimycobacterial Compound, N -Octanesulfonylacetamide, and Its Effects on Lipid and Mycolic Acid Synthesis

Parrish¹,

Houston

Jones

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

␤-Sulfonyl carboxamides have been proposed to serve as transition-state analogues of the ␤-ketoacyl synthase reaction involved in fatty acid elongation. We tested the efficacy of N-octanesulfonylacetamide (OSA) as an inhibitor of fatty acid and mycolic acid biosynthesis in mycobacteria. Using the BACTEC radiometric growth system, we observed that OSA inhibits the growth of several species of slow-growing mycobacteria, including Mycobacterium tuberculosis (H37Rv and clinical isolates), the Mycobacterium avium complex (MAC), Mycobacterium bovis BCG, Mycobacterium kansasii, and others. Nearly all species and strains tested, including isoniazid and multidrug resistant isolates of M. tuberculosis, were susceptible to OSA, with MICs ranging from 6.25 to 12.5 g/ml. Only three clinical isolates of M. tuberculosis (CSU93, OT2724, and 401296), MAC, and Mycobacterium paratuberculosis required an OSA MIC higher than 25.0 g/ml. Rapid-growing mycobacterial species, such as Mycobacterium smegmatis, Mycobacterium fortuitum, and others, were not susceptible at concentrations of up to 100 g/ml. A 2-dimensional thin-layer chromatography system showed that OSA treatment resulted in a significant decrease in all species of mycolic acids present in BCG. In contrast, mycolic acids in M. smegmatis were relatively unaffected following exposure to OSA. Other lipids, including polar and nonpolar extractable classes, were unchanged following exposure to OSA in both BCG and M. smegmatis. Transmission electron microscopy of OSA-treated BCG cells revealed a disruption in cell wall synthesis and incomplete septum formation. Our results indicate that OSA inhibits the growth of several species of mycobacteria, including both isoniazid-resistant and multidrug resistant strains of M. tuberculosis. This inhibition may be the result of OSA-mediated effects on mycolic acid synthesis in slow-growing mycobacteria or inhibition via an undescribed mechanism. Our results indicate that OSA may serve as a promising lead compound for future antituberculous drug development.

show abstract

Antimycobacterial activity of cerulenin and its effects on lipid biosynthesis

Cited by 42 publications

References 19 publications

Characterization of Mycobacterium smegmatis Expressing the Mycobacterium tuberculosis Fatty Acid Synthase I ( fas1 ) Gene

Characterization of Mycobacterium smegmatis Expressing the Mycobacterium tuberculosis Fatty Acid Synthase I ( fas1 ) Gene

Increased Vancomycin Susceptibility in Mycobacteria: a New Approach To Identify Synergistic Activity against Multidrug-Resistant Mycobacteria

In Vitro Activity of a Novel Antimycobacterial Compound, N -Octanesulfonylacetamide, and Its Effects on Lipid and Mycolic Acid Synthesis

Contact Info

Product

Resources

About