95398-45-1 Usage
Description
A-54556A is an acyldepsipeptide (ADEP) antibiotic that has been found in Streptomyces hawaiiensis. It is active against B. subtilis, S. pyogenes, and E. faecalis, as well as penicillin-resistant S. pneumoniae, vancomycin-resistant E. faecium, and methicillin-resistant S. aureus (MRSA; IC50s = 0.2, 0.4, 0.4, 1.6, 0.4, and 6.3 μg/ml, respectively). It binds to and activates caseinolytic protease P (ClpP), inducing degradation of β-casein by the B. subtilis ClpP in an ATPase-independent manner when used at concentrations of 2.5 and 5 μg/ml.
Uses
A 54556A is an unusual depsipeptide isolated from Streptomyces hawaiiensis by researchers at Eli Lilly in 1985, featuring a trienone side chain. A 54556A is potently active against Gram positive and Gram negative bacteria, including MRSA. A 54556A was the original lead structure of the recently re-discovered acyldepsipeptide (ADEP) antibiotics that act by activating and disregulating Clp-family proteins. ADEPs are considered important leads in the development of new generations of antibiotics against resistant bacteria.
in vitro
previous study found that the treatment of b. subtilis with 1.6 mg/ml of a-54556a reduced the number of viable cells by 2 log units. in addition, the biosynthesis of dna, rna, protein, cell wall and fatty acid proceeded unhindered for 1 h at 2 mg/ml a-54556a, whereas classical antibiotics were clearly distinguished by preferential inhibition of their target pathway. microscopic examination showed that after addition of a-54556a at concentrations as low as 0.4 mg/ml, b. subtilis started to form filaments [1].
in vivo
two a-54556a analogs, adep 2 and adep 4, were proven to be active in the treatment of bacterial infections in rodents. when mice were challenged with a lethal systemic infection of e. faecalis, 1 mg/kg adep 2 or 0.5 mg/kg adep 4 were sufficient for 100% survival. in lethal sepsis caused by s. aureus, 12.5 mg/kg adep 4 rescued 80% of the mice and reduced the bacterial loads in liver, spleen and lung by 2–3 log units compared to an untreated control [1].
IC 50
0.2 μg/ml for bacillus subtilis 168
references
[1] h. brtz-oesterhelt, d. beyer, h. p. kroll, et al. dysregulation of bacterial proteolytic machinery by a new class of antibiotics. nature medicine 11(10), 1082-1087 (2005).
Check Digit Verification of cas no
The CAS Registry Mumber 95398-45-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 9,5,3,9 and 8 respectively; the second part has 2 digits, 4 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 95398-45:
(7*9)+(6*5)+(5*3)+(4*9)+(3*8)+(2*4)+(1*5)=181
181 % 10 = 1
So 95398-45-1 is a valid CAS Registry Number.
95398-45-1Relevant articles and documents
Total synthesis and antibacterial testing of the A54556 cyclic acyldepsipeptides isolated from streptomyces hawaiiensis
Goodreid, Jordan D.,Wong, Keith,Leung, Elisa,McCaw, Shannon E.,Gray-Owen, Scott D.,Lough, Alan,Houry, Walid A.,Batey, Robert A.
, p. 2170 - 2181 (2014)
The first total synthesis of all six known A54556 acyldepsipeptide (ADEP) antibiotics from Streptomyces hawaiiensis is reported. This family of compounds has a unique mechanism of antibacterial action, acting as activators of caseinolytic protease (ClpP). Assembly of the 16-membered depsipeptide core was accomplished via a pentafluorophenyl ester-based macrolactamization strategy. Late stage amine deprotection was carried out under neutral conditions by employing a mild hydrogenolysis strategy, which avoids the formation of undesired ring-opened depsipeptide side products encountered during deprotection of acid-labile protecting groups. The free amines were found to be significantly more reactive toward late stage amide bond formation as compared to the corresponding ammonium salts, giving final products in excellent yields. A thorough NMR spectroscopic analysis of these compounds was carried out to formally assign the structures and to aid with the spectroscopic assignment of ADEP analogues. The identity of two of the structures was confirmed by comparison with biologically produced samples from S. hawaiiensis. An X-ray crystallographic analysis of an ADEP analogue reveals a conformation similar to that found in cocrystal structures of ADEPs with ClpP protease. The degree of antibacterial activity of the different compounds was evaluated in vitro using MIC assays employing both Gram-positive and Gram-negative strains and a fluorescence-based biochemical assay.
