Cholic Acid-Derived Amphiphile which Combats Gram-Positive Bacteria-Mediated Infections via Disintegration of Lipid Clusters

被引：23

作者：

Kumar, Sandeep ^{[1
,2
]}

Thakur, Jyoti ^{[3
]}

Yadav, Kavita ^{[1
,2
]}

Mitra, Madhurima ^{[1
]}

Pal, Sanjay ^{[1
,4
]}

Ray, Arjun ^{[5
,9
]}

Gupta, Siddhi ^{[1
]}

Medatwal, Nihal ^{[1
]}

Gupta, Ragini ^{[1
]}

Mishra, Deepakkumar ^{[1
]}

Rani, Parul ^{[1
]}

Padhi, Siladitya ^{[6
]}

Sharma, Priyanka ^{[7
]}

Kapil, Arti ^{[7
]}

Srivastava, Aasheesh ^{[3
]}

Priyakumar, U. Deva ^{[6
]}

Dasgupta, Ujjaini ^{[8
]}

Thukral, Lipi ^{[5
]}

Bajaj, Avinash ^{[1
]}

机构：

[1] NCR Biotech Sci Cluster, Lab Nanotechnol & Chem Biol, Reg Ctr Biotechnol, 3rd Milestone Faridabad Gurgaon Expressway, Faridabad 121001, Haryana, India

[2] Manipal Acad Higher Educ, Tiger Circle Rd, Manipal 576104, Karnataka, India

[3] Indian Inst Sci Educ & Res, Dept Chem, Bhopal Bypass Rd, Bhopal 462066, Madhya Pradesh, India

[4] Kalinga Inst Ind Technol, KIIT Rd, Bhubaneswar 751024, Odisha, India

[5] CSIR Inst Genom & Integrat Biol, Inst Genom & Integrat Biol, South Campus,Mathura Rd, New Delhi 110025, India

[6] Int Inst Informat Technol, Ctr Computat Nat Sci & Bioinformat, Prof CR Rao Rd, Hyderabad 500032, India

[7] All India Inst Med Sci, Dept Microbiol, Sri Aurobindo Marg, New Delhi 110029, India

[8] Amity Univ, Amity Inst Integrat Sci & Hlth, Amity Educ Valley Gurugram, Gurugram 122413, Haryana, India

[9] Indraprastha Inst Informat Technol, Ctr Computat Biol, Okhla Ind Estate,Phase 3, New Delhi 110020, India

来源：

ACS BIOMATERIALS SCIENCE & ENGINEERING | 2019年 / 5卷 / 09期

关键词：

antibacterial; bile acids; membrane interactions; MD simulations; antimicrobials; NEGATIVE BACTERIA; FORCE-FIELD; ANTIBACTERIAL; PEPTIDES; DESIGN; CHARMM; RESISTANCE; MOLECULES; BIOFILMS; MIMICS;

D O I：

10.1021/acsbiomaterials.9b00706

中图分类号：

TB3 [工程材料学]; R318.08 [生物材料学];

学科分类号：

0805 ; 080501 ; 080502 ;

摘要：

Inappropriate and uncontrolled use of antibiotics results in the emergence of antibiotic resistance, thereby threatening the present clinical regimens to treat infectious diseases. Therefore, new antimicrobial agents that can prevent bacteria from developing drug resistance are urgently needed. Selective disruption of bacterial membranes is the most effective strategy for combating microbial infections as accumulation of genetic mutations will not allow for the emergence of drug resistance against these antimicrobials. In this work, we tested cholic acid (CA) derived amphiphiles tethered with different alkyl chains for their ability to combat Gram-positive bacterial infections. In-depth biophysical and biomolecular simulation studies suggested that the amphiphile with a hexyl chain (6) executes more effective interactions with Gram-positive bacterial membranes as compared to other hydrophobic counterparts. Amphiphile 6 is effective against multidrug resistant Gram-positive bacterial strains as well and does not allow the adherence of S. aureus on amphiphile 6 coated catheters implanted in mice. Further, treatment of wound infections with amphiphile 6 clears the bacterial infections. Therefore, the current study presents strategic guidelines in design and development of CA-derived membrane-targeting antimicrobials for Gram-positive bacterial infections.

引用

页码：4764 / 4775

页数：23

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