Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors

Takhi, Mohamed; Sreenivas, Kandepu; Reddy, Chandrashekar K.; Munikumar, Mahadari; Praveena, Kolakota; Sudheer, P; Rao, Bandaru Narasinga; Ramakanth, Gollamudi; Sivaranjani, Jampala; Mulik, Shardaprasad; Reddy, Yeruva R.; Rao, K.N.; Pallavi, Rentala; Lakshminarasimhan, Anirudha; Panigrahi, Sunil K.; Antony, Thomas; Abdullah, Iskandar; Lee, Yean Kee; Ramachandra, Murali; Yusof, Rohana; Rahman, Noorsaadah Abd.; Subramanya, Hosahalli

doi:10.1016/j.ejmech.2014.07.036

Cited by 28 publications

(22 citation statements)

References 31 publications

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“…The effectiveness of FabI inhibition is best exemplified by triclosan, which has been broadly used in consumer and medical goods for decades (14,15). FASII inhibitors demonstrate various degrees of efficacy in murine models of S. aureus infection (11,13,(16)(17)(18)(19). This variability is likely due to the ability of S. aureus to resist FASII inhibition by incorporating host-derived fatty acids (20)(21)(22).…”

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confidence: 99%

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

et al. 2018

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Methicillin-resistant (MRSA) is a threat to global health. Consequently, much effort has focused on the development of new antimicrobials that target novel aspects of physiology. Fatty acids are required to maintain cell viability, and bacteria synthesize fatty acids using the type II fatty acid synthesis pathway (FASII). FASII is significantly different from human fatty acid synthesis, underscoring the therapeutic potential of inhibiting this pathway. However, many Gram-positive pathogens incorporate exogenous fatty acids, bypassing FASII inhibition and leaving the clinical potential of FASII inhibitors uncertain. Importantly, the source(s) of fatty acids available to pathogens within the host environment remains unclear. Fatty acids are transported throughout the body by lipoprotein particles in the form of triglycerides and esterified cholesterol. Thus, lipoproteins, such as low-density lipoprotein (LDL) represent a potentially rich source of exogenous fatty acids for during infection. We sought to test the ability of LDLs to serve as a fatty acid source for and show that cells cultured in the presence of human LDLs demonstrate increased tolerance to the FASII inhibitor, triclosan. Using mass spectrometry, we observed that host-derived fatty acids present in the LDLs are incorporated into the staphylococcal membrane and that tolerance to triclosan is facilitated by the fatty acid kinase A, FakA, and Geh, a triacylglycerol lipase. Finally, we demonstrate that human LDLs support the growth of fatty acid auxotrophs. Together, these results suggest that human lipoprotein particles are a viable source of exogenous fatty acids for during infection. Inhibition of bacterial fatty acid synthesis is a promising approach to combating infections caused by and other human pathogens. However, incorporates exogenous fatty acids into its phospholipid bilayer. Therefore, the clinical utility of targeting bacterial fatty acid synthesis is debated. Moreover, the fatty acid reservoir(s) exploited by are not well understood. Human low-density lipoprotein particles represent a particularly abundant source of fatty acids and are present in tissues colonizes. Herein, we establish that is capable of utilizing the fatty acids present in low-density lipoproteins to bypass both chemical and genetic inhibition of fatty acid synthesis. These findings imply that targets LDLs as a source of fatty acids during pathogenesis.

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confidence: 99%

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

et al. 2018

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“…This protein contains an iron protoporphyrin moiety located at the active site, and our compounds may bind to the iron atom via a nitrogen atom in the nicotinamide ring. After reviewing the different chemical classes that docked into the enoyl reductase active site, such as amides, triazoles, azoles, and pyridone derivatives [ 30 , 31 , 32 , 33 ], we examined our compounds on the active site because some structural similarities exist. The same was done with respect to the cytochrome P450 14-α-sterol demethylase active site, which was examined with different groups of compounds from different chemical classes, such as imidazoles, pyrimidines, triazoles, thiosemicarbazides, and acetamide derivatives [ 34 , 35 , 36 , 37 ].…”

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confidence: 99%

Synthesis, Molecular Docking Studies, In Vitro Antimicrobial and Antifungal Activities of Novel Dipeptide Derivatives Based on N-(2-(2-Hydrazinyl-2-oxoethylamino)-2-oxoethyl)-Nicotinamide

et al. 2018

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A series of linear dipeptide derivatives (4–10) were prepared and evaluated as antimicrobial agents via the synthesis of N-(2-(2-hydrazinyl-2-oxoethylamino)-2-oxoethyl) nicotinamide (4). Compound 4 was reacted with 4-chlorobenzaldehyde or 4-hydroxybenzaldehyde, to give the hydrazones 5 and 6, respectively. On the other hand, Compound 4 was coupled with phenylisocyanate or methylisothiocyanate to give Compounds 7 and 8, respectively. The latter compounds (7 and 8) were coupled with chloroacetic acid to give oxazolidine (9) and thiazolidine (10), respectively. The newly synthesized dipeptide compounds were confirmed by means of their spectral data. The antimicrobial activity of the newly synthesized compounds 4–10 was evaluated by agar well diffusion, and they showed good activity. Compounds 4, 5, and 9 gave the most promising activity in this study. Most of the tested compounds possessed MIC values ranging from 50 to 500 µg/mL. Furthermore, docking studies were carried out on enoyl reductase from E. coli and cytochrome P450 14 α-sterol demethylase (Cyp51) from Candida albicans active sites. The MolDock scores of the seven tested compounds ranged between −117 and −171 and between −107 and −179, respectively.

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“…The overall structure of BpmFabI in complex with AFN‐1252 is similar to the earlier reported apo‐structure of Bpm FabI (PDB:3EK2) and ternary complex structures of Ec (E. coli : PDB:4JQC), and SaFabI (PDB:4FS3) with AFN‐1252 and NAD/NADPH . Multiple attempts to crystallize the ternary complex of BpmFabI with NAD/NADH and AFN‐1252 were not successful.…”

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confidence: 99%

AFN‐1252 is a potent inhibitor of enoyl‐ACPreductase fromBurkholderia pseudomallei—Crystal structure, mode of action, and biological activity

et al. 2015

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Melioidosis is a tropical bacterial infection caused by Burkholderia pseudomallei (B. pseudomallei; Bpm), a Gram-negative bacterium. Current therapeutic options are largely limited to trimethoprim-sulfamethoxazole and b-lactam drugs, and the treatment duration is about 4 months. Moreover, resistance has been reported to these drugs. Hence, there is a pressing need to develop new antibiotics for Melioidosis. Inhibition of enoyl-ACP reducatase (FabI), a key enzyme in the fatty acid biosynthesis pathway has shown significant promise for antibacterial drug development. FabI has been identified as the major enoyl-ACP reductase present in B. pseudomallei. In this study, we evaluated AFN-1252, a Staphylococcus aureus FabI inhibitor currently in clinical development, for its potential to bind to BpmFabI enzyme and inhibit B. pseudomallei bacterial growth. AFN-1252 stabilized BpmFabI and inhibited the enzyme activity with an IC 50 of 9.6 nM. It showed good antibacterial activity against B. pseudomallei R15 strain, isolated from a melioidosis patient (MIC of 2.35 mg/L). X-ray structure of BpmFabI with AFN-1252 was determined at a resolution of 2.3 Å . Complex of BpmFabI with AFN-1252 formed a symmetrical tetrameric structure with one molecule of AFN-1252 bound to each monomeric subunit. The kinetic and thermal melting studies supported the finding that AFN-1252 can bind to BpmFabI independent of cofactor. The structural and mechanistic insights from these studies might help the rational design and development of new FabI inhibitors.

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Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors

Cited by 28 publications

References 31 publications

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

Staphylococcus aureus Utilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

Synthesis, Molecular Docking Studies, In Vitro Antimicrobial and Antifungal Activities of Novel Dipeptide Derivatives Based on N-(2-(2-Hydrazinyl-2-oxoethylamino)-2-oxoethyl)-Nicotinamide

AFN‐1252 is a potent inhibitor of enoyl‐ACPreductase fromBurkholderia pseudomallei—Crystal structure, mode of action, and biological activity

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