Amphipathic Peptide Antibiotics with Potent Activity against Multidrug-Resistant Pathogens

Published on Mar 24, 2021in Pharmaceutics4.421
· DOI :10.3390/PHARMACEUTICS13040438
Jingru Shi2
Estimated H-index: 2
Chen Chen + 3 AuthorsLiu Yuan
The emergence and prevalence of multidrug-resistant (MDR) bacteria have posed a serious threat to public health. Of particular concern are methicillin-resistant Staphylococcus aureus (MRSA) and blaNDM, mcr-1 and tet(X)-positive Gram-negative pathogens. The fact that few new antibiotics have been approved in recent years exacerbates this global crisis, thus, new alternatives are urgently needed. Antimicrobial peptides (AMPs) originated from host defense peptides with a wide range of sources and multiple functions, are less prone to achieve resistance. All these characteristics laid the foundation for AMPs to become potential antibiotic candidates. In this study, we revealed that peptide WW307 displayed potent antibacterial and bactericidal activity against MDR bacteria, including MRSA and Gram-negative bacteria carrying blaNDM-5, mcr-1 or tet(X4). In addition, WW307 exhibited great biofilm inhibition and eradication activity. Safety and stability experiments showed that WW307 had a strong resistance against various physiological conditions and displayed relatively low toxicity. Mechanistic experiments showed that WW307 resulted in membrane damage by selectively targeting bacterial membrane-specific components, including lipopolysaccharide (LPS), phosphatidylglycerol (PG), and cardiolipin (CL). Moreover, WW307 dissipated membrane potential and triggered the production of reactive oxygen species (ROS). Collectively, these results demonstrated that WW307 represents a promising candidate for combating MDR pathogens.
#1Shuimu Lin (Guangzhou Medical University)H-Index: 1
#2John D. Wade (University of Melbourne)H-Index: 50
Last. Shouping Liu (Guangzhou Medical University)H-Index: 1
view all 3 authors...
ConspectusThe alarming rate at which pathogens are developing resistance to conventional antibiotics represents one of the major global challenges to public health care. The prevalence of multidrug-resistant microorganisms is a major impetus for the discovery and development of new antimicrobials. Nature has, to date, been the source of most of the antibiotics discovered and used, including cationic antimicrobial peptides (CAMPs). CAMPs are key components of the innate immune system that are wid...
2 CitationsSource
#1Liu Yuan (Ministry of Education)
#1Yuan Liu (YZU: Yangzhou University)H-Index: 9
Last. Zhiqiang Wang (YZU: Yangzhou University)H-Index: 8
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The antibiotic resistance crisis is becoming incredibly thorny due to the indiscriminate employment of antibiotics in agriculture and aquaculture, such as growth promoters, and the emergence of bacteria that are capable of enduring antibiotic treatment in an endless stream. Hence, to reverse this situation, vigorous efforts should be made in the process of identifying other alternative strategies with a lower frequency of resistance. Antimicrobial peptides (AMPs), originated from host defense pe...
2 CitationsSource
#1Erica J. Zheng (Broad Institute)H-Index: 2
#2Jonathan M. Stokes (MIT: Massachusetts Institute of Technology)H-Index: 10
Last. James J. CollinsH-Index: 129
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Summary The vast majority of bactericidal antibiotics display poor efficacy against bacterial persisters, cells that are in a metabolically repressed state. Molecules that retain their bactericidal functions against such bacteria often display toxicity to human cells, which limits treatment options for infections caused by persisters. Here, we leverage insight into metabolism-dependent bactericidal antibiotic efficacy to design antibiotic combinations that sterilize both metabolically active and...
7 CitationsSource
#1Yangbin Liang (SCUT: South China University of Technology)H-Index: 1
#2Xinshuang Zhang (SCUT: South China University of Technology)H-Index: 1
Last. Meng-Hua Xiong (SCUT: South China University of Technology)H-Index: 20
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Since the development of bacterial resistance, the decreasing effectiveness of antibiotics is becoming one of the most critical problems in the worldwide. Novel antibacterial agents are urgently needed to prevent humanity from declining into the “post-antibiotic era”. As an important part of the innate immune system, antimicrobial peptides (AMPs) are one of the most promising antibacterial agents with its broad-spectrum activity against bacteria and low propensity for drug resistance. However, t...
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#1Yuan Liu (YZU: Yangzhou University)H-Index: 9
#2Jingru Shi (YZU: Yangzhou University)H-Index: 2
Last. Zhiqiang Wang (YZU: Yangzhou University)H-Index: 8
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#1Yuan LiuH-Index: 9
#2Yuqian JiaH-Index: 3
Last. Zhiqiang Wang (YZU: Yangzhou University)H-Index: 8
view all 11 authors...
3 CitationsSource
#1Margit Mahlapuu (KI: Karolinska Institutet)H-Index: 25
#2Camilla Björn (Research Institutes of Sweden)H-Index: 2
Last. Jonas Ekblom (KI: Karolinska Institutet)H-Index: 1
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The rapid development of microbial resistance to conventional antibiotics has accelerated efforts to find anti-infectives with a novel mode-of-action, which are less prone to bacterial resistance. ...
11 CitationsSource
#1Jayaram Lakshmaiah Narayana (UNMC: University of Nebraska Medical Center)H-Index: 9
#2Biswajit Mishra (UNMC: University of Nebraska Medical Center)H-Index: 22
Last. Guangshun Wang (UNMC: University of Nebraska Medical Center)H-Index: 32
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Antimicrobial peptides are important candidates for developing new classes of antibiotics because of their potency against antibiotic-resistant pathogens. Current research focuses on topical applications and it is unclear how to design peptides with systemic efficacy. To address this problem, we designed two potent peptides by combining database-guided discovery with structure-based design. When bound to membranes, these two short peptides with an identical amino acid composition can adopt two d...
9 CitationsSource
#1Surajit Bhattacharjya (NTU: Nanyang Technological University)H-Index: 27
#2Suzana K. Straus (UBC: University of British Columbia)H-Index: 29
In an era where the pipeline of new antibiotic development is drying up, the continuous rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) bacteria are genuine threats to human health. Although antimicrobial peptides (AMPs) may serve as promising leads against drug resistant bacteria, only a few AMPs are in advanced clinical trials. The limitations of AMPs, namely their low in vivo activity, toxicity, and poor bioavailability, need to be addressed. Here, we review engineerin...
10 CitationsSource
#1Yongjie Zhu (NEAU: Northeast Agricultural University)H-Index: 4
#2Changxuan Shao (NEAU: Northeast Agricultural University)H-Index: 7
Last. Anshan Shan (NEAU: Northeast Agricultural University)H-Index: 20
view all 8 authors...
Antimicrobial peptides (AMPs) are expected to solve problem of antibiotic resistance due to their distinctive nonspecific membrane-disruptive mechanism. However, clinical application of AMPs has been precluded by their poor stability, although various complex chemical strategies have been employed to solve this problem, and this undoubtedly greatly increases the manufacturing cost. Herein, a series of novel peptides with high stability were developed based on protease-specific cleavage sites and...
3 CitationsSource
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