New design platform for malonyl‐CoA‐acyl carrier protein transacylase

Hong, Suc-Kyoung; Kim, Kook Han; Park, Joon Kyu; Jeong, Ki-Woong; Kim, Yangmee; Kim, Eunice EunKyeong

doi:10.1016/j.febslet.2010.02.038

Cited by 21 publications

(13 citation statements)

References 25 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sequencing fabD of other FA-T R CondT R clones revealed mutations mainly at position G196, and one at position Q265 ( Table 1 ). FabD G196 is adjacent to key residues (positions 198 and 199) of the FabD active site based on S. aureus FabD crystallography 41 ; it is possible that substitution by less flexible amino acids than glycine might impose constraints on FabD activity. The Q265P mutation is within a conserved region separating a helix from a β-strand as suggested from Escherichia coli FabD structure 42 .…”

Section: Resultsmentioning

confidence: 99%

Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials

et al. 2016

View full text Add to dashboard Cite

The bacterial pathway for fatty acid biosynthesis, FASII, is a target for development of new anti-staphylococcal drugs. This strategy is based on previous reports indicating that self-synthesized fatty acids appear to be indispensable for Staphylococcus aureus growth and virulence, although other bacteria can use exogenous fatty acids to compensate FASII inhibition. Here we report that staphylococci can become resistant to the FASII-targeted inhibitor triclosan via high frequency mutations in fabD, one of the FASII genes. The fabD mutants can be conditional for FASII and not require exogenous fatty acids for normal growth, and can use diverse fatty acid combinations (including host fatty acids) when FASII is blocked. These mutants show cross-resistance to inhibitors of other FASII enzymes and are infectious in mice. Clinical isolates bearing fabD polymorphisms also bypass FASII inhibition. We propose that fatty acid-rich environments within the host, in the presence of FASII inhibitors, might favour the emergence of staphylococcal strains displaying resistance to multiple FASII inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Nonauxotrophy of these isolates might be due to supplementary accBC copies (which are present in numerous staphylococcal genomes) and/or to partial accD read-through (e.g., the accD stop in Trsa 36 corresponds to a single-nucleotide deletion in a stretch of six adenines). About half of the Exo isolates studied here carried fabD polymorphisms, some of which mapped adjacent to a catalytic residue of the active site (Table 1) (31). Two isolates had the FabD G196R mutation (the more common amino acid at position 196 [aa 196] is glycine) that we recently showed to be responsible for FASII bypass (19).…”

Section: Resultsmentioning

confidence: 99%

Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

Gloux

Guillemet

Soler

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The need for new antimicrobials to treat bacterial infections has led to the use of type II fatty acid synthesis (FASII) enzymes as front-line targets. However, recent studies suggest that FASII inhibitors may not work against the opportunist pathogen Staphylococcus aureus, as environmental fatty acids favor emergence of multi-anti-FASII resistance. As fatty acids are abundant in the host and one FASII inhibitor, triclosan, is widespread, we investigated whether fatty acid pools impact resistance in clinical and veterinary S. aureus isolates. Simple addition of fatty acids to the screening medium led to a 50% increase in triclosan resistance, as tested in 700 isolates. Moreover, nonculturable triclosan-resistant fatty acid auxotrophs, which escape detection under routine conditions, were uncovered in primary patient samples. FASII bypass in selected isolates correlated with polymorphisms in the acc and fabD loci. We conclude that fatty-acid-dependent strategies to escape FASII inhibition are common among S. aureus isolates and correlate with anti-FASII resistance and emergence of nonculturable variants.KEYWORDS antibiotic resistance, infection, persistence, nondetectable resistance, fatty acids, Staphylococcus aureus S taphylococcus aureus is a leading cause of a wide range of infections that can affect numerous host organs and cause a range of effects from mild symptoms to severe and life-threatening diseases. Acquisition of antimicrobial resistance, likely due to overuse of antibiotics, is the principal cause of S. aureus drug resistance (1). A class of new-generation antimicrobials in intensive development uses the type II fatty acid synthesis (FASII) pathway as an antibacterial target (2-5) to treat S. aureus infections (6-8). A widely used biocide, triclosan (5-chloro-2-[2,4-dichlorophenoxy]phenol; commercialized as Irgasan or Microban), is a prototype for further anti-FASII development (4, 9, 10).The utility of FASII inhibitors was questioned when several Gram-positive bacteria were shown to be refractory to FASII inhibitors in the presence of exogenous fatty acids, making FASII enzymes dispensable (11,12). Both free and complexed fatty acids are abundant in the host (13,14), which would facilitate FASII bypass. Reservoirs and invasion sites of clinical and community-acquired staphylococci (i.e., skin, nares, gut, blood, and organs) are naturally rich in fatty acids (13-16), and triclosan is present in the environment and in human body fluids (17,18). This combination could favor FASII bypass via emergence of triclosan-resistant variants, including fatty acid auxotrophs. Fatty-acid-dependent isolates escape detection on standard isolation media, thereby confounding diagnosis and treatment.

show abstract

“…Malonyl‐CoA acyl carrier protein transacylase (MCAT, EC 2.3.1.39) is proposed to be a critical enzyme in the type II fatty acid synthesis (FAS II) pathway . Previous studies on MCAT are generally focused on its crystal structure, for instance, the crystal structure of MCAT in Helicobacter pylori and Staphylococcus aureus . However, very little is known about the microalgal MCAT and its functional role in fatty acid biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

Identification of a malonyl CoA‐acyl carrier protein transacylase and its regulatory role in fatty acid biosynthesis in oleaginous microalga Nannochloropsis oceanica

Chen

Liu

et al. 2017

Biotech and App Biochem

View full text Add to dashboard Cite

Oleaginous microalgae hold great promises for biofuel production. However, commercialization of microalgal biofuels remains impracticable due to the lack of suitable industrial strains with high growth rate and lipid productivity. Engineering of metabolic pathways is a potential strategy for the improvement of microalgal strains for the production of lipids and also value-added products in microalgae. Malonyl CoA-acyl carrier protein transacylase (MCAT) has been reported to be involved in fatty acid biosynthesis. Here, we identified a putative MCAT in the oleaginous marine microalga Nannochloropsis oceanica. NoMCAT overexpressing N. oceanica showed a higher growth rate and photosynthetic efficiency. The neutral lipid content of engineered lines showed a significant increase by up to 31% compared to wild type. Gas chromatography-mass spectrometry analysis revealed that NoMCAT overexpression significantly altered the fatty acid composition. The composition of eicosapentaenoic acid (C20:5), which is a polyunsaturated fatty acid necessary for animal nutrition, increased by 8%. These results demonstrate the role of MCAT in enhancing fatty acid biosynthesis and growth in microalgae, and also provide an insight into metabolic engineering of microalgae with high industrial potential.

show abstract

New design platform for malonyl‐CoA‐acyl carrier protein transacylase

Cited by 21 publications

References 25 publications

Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials

Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials

Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

Identification of a malonyl CoA‐acyl carrier protein transacylase and its regulatory role in fatty acid biosynthesis in oleaginous microalga Nannochloropsis oceanica

Contact Info

Product

Resources

About