scholarly journals Translocation of non-lytic antimicrobial peptides and bacteria penetrating peptides across the inner membrane of the bacterial envelope

2021 ◽  
Author(s):  
Jakob Frimodt-Møller ◽  
Christopher Campion ◽  
Peter E. Nielsen ◽  
Anders Løbner-Olesen
Keyword(s):  
Antimicrobial Peptides ◽  
Pathogenic Bacteria ◽  
Cytoplasmic Membrane ◽  
Cell Envelope ◽  
Multidrug Resistant ◽  
Great Promise ◽  
Strong Focus ◽  
Gene Transcripts ◽  
Phosphorodiamidate Morpholino Oligomers ◽  
Intracellular Targets

AbstractThe increase in multidrug-resistant pathogenic bacteria has become a problem worldwide. Currently there is a strong focus on the development of novel antimicrobials, including antimicrobial peptides (AMP) and antimicrobial antisense agents. While the majority of AMP have membrane activity and kill bacteria through membrane disruption, non-lytic AMP are non-membrane active, internalize and have intracellular targets. Antimicrobial antisense agents such as peptide nucleic acids (PNA) and phosphorodiamidate morpholino oligomers (PMO), show great promise as novel antibacterial agents, killing bacteria by inhibiting translation of essential target gene transcripts. However, naked PNA and PMO are unable to translocate across the cell envelope of bacteria, to reach their target in the cytosol, and are conjugated to bacteria penetrating peptides (BPP) for cytosolic delivery. Here, we discuss how non-lytic AMP and BPP-PMO/PNA conjugates translocate across the cytoplasmic membrane via receptor-mediated transport, such as the cytoplasmic membrane transporters SbmA, MdtM/YjiL, and/or YgdD, or via a less well described autonomous process.

Genomic fitness profiling of Acinetobacter baumannii reveals modes of action for common biocides and mechanisms of biocide-antibiotic antagonism

2021 ◽  
Author(s):  
Liping Li ◽  
Francesca Short ◽  
Karl Hassan ◽  
Varsha Naidu ◽  
Alaska Pokhrel ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Pathogenic Bacteria ◽  
Cell Envelope ◽  
Tricarboxylic Acid Cycle ◽  
Insertion Site ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Cell Respiration ◽  
Community Environments ◽  
Intracellular Targets

Abstract Biocides, such as antiseptics and disinfectants, are used ubiquitously for hygiene in households and for life-saving infection control in hospitals. An increasing concern is that the widespread use of biocides may contribute to the emergence and spread of multidrug-resistant bacteria. We performed transposon directed insertion site sequencing (TraDIS) to identify genes and key cellular pathways of the multidrug resistant nosocomial pathogen Acinetobacter baumannii, that affect host fitness during exposure to a panel of ten structurally-diverse and clinically-relevant biocides: silver nitrate, benzalkonium, cetyltrimethylammonium bromide (CTAB), chlorhexidine, triclosan, chloroxylenol, polyvidone iodine, bleach, glutaraldehyde and ethanol. Multiple genes encoding proteins localised either in the cell envelope or in the cytoplasm were shown to affect biocide susceptibility. These proteins are involved in multiple processes including fatty acid biogenesis, multidrug efflux, the tricarboxylic acid cycle, cell respiration and cell division, suggesting that these biocides may have intracellular targets in addition to their known effects on the cell envelope. Based on the importance of cell respiration genes for A. baumannii fitness on biocides, we proposed and confirmed that apart from triclosan, the other 9 biocides at sub-inhibitory concentration can dissipate the membrane potential and lead to A. baumannii tolerance to antibiotics that have intracellular targets. Our results support the concern that residual biocides in clinical or community environments can promote the development of antibiotic resistance in pathogenic bacteria.

Using chemical synthesis to optimise antimicrobial peptides in the fight against antimicrobial resistance

2019 ◽  
Vol 91 (2) ◽  
pp. 181-198 ◽  
Author(s):  
Freda F. Li ◽  
Margaret A. Brimble
Keyword(s):  
Antimicrobial Peptides ◽  
Multidrug Resistant ◽  
Great Promise ◽  
Resistant Bacteria ◽  
Manufacturing Cost ◽  
Animal Cells ◽  
Design And Synthesis ◽  
Living Organisms ◽  
High Manufacturing Cost ◽  
Natural Peptides

Abstract The emergence of multidrug-resistant bacteria has necessitated the urgent need for novel antibacterial agents. Antimicrobial peptides (AMPs), the host-defence molecules of most living organisms, have shown great promise as potential antibiotic candidates due to their multiple mechanisms of action which result in very low or negligible induction of resistance. However, the development of AMPs for clinical use has been limited by their potential toxicity to animal cells, low metabolic stability and high manufacturing cost. Extensive efforts have therefore been directed towards the development of enhanced variants of natural AMPs to overcome these aforementioned limitations. In this review, we present our efforts focused on development of efficient strategies to prepare several recently discovered AMPs including antitubercular peptides. The design and synthesis of more potent and stable AMP analogues with synthetic modifications made to the natural peptides containing glycosylated residues or disulfide bridges are described.

scholarly journals Nanostructured Antimicrobial Peptides: Crucial Steps of Overcoming the Bottleneck for Clinics

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhanyi Yang ◽  
Shiqi He ◽  
Hua Wu ◽  
Ting Yin ◽  
Lili Wang ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Controlled Release ◽  
Antimicrobial Peptides ◽  
Biological Activities ◽  
Antimicrobial Properties ◽  
Multidrug Resistant ◽  
Great Promise ◽  
Resistant Bacteria ◽  
Biological Stability ◽  
Security Issue

The security issue of human health is faced with dispiriting threats from multidrug-resistant bacteria infections induced by the abuse and misuse of antibiotics. Over decades, the antimicrobial peptides (AMPs) hold great promise as a viable alternative to treatment with antibiotics due to their peculiar antimicrobial mechanisms of action, broad-spectrum antimicrobial activity, lower drug residue, and ease of synthesis and modification. However, they universally express a series of disadvantages that hinder their potential application in the biomedical field (e.g., low bioavailability, poor protease resistance, and high cytotoxicity) and extremely waste the abundant resources of AMP database discovered over the decades. For all these reasons, the nanostructured antimicrobial peptides (Ns-AMPs), based on a variety of nanosystem modification, have made up for the deficiencies and pushed the development of novel AMP-based antimicrobial therapies. In this review, we provide an overview of the advantages of Ns-AMPs in improving therapeutic efficacy and biological stability, reducing side effects, and gaining the effect of organic targeting and drug controlled release. Then the different material categories of Ns-AMPs are described, including inorganic material nanosystems containing AMPs, organic material nanosystems containing AMPs, and self-assembled AMPs. Additionally, this review focuses on the Ns-AMPs for the effect of biological activities, with emphasis on antimicrobial activity, biosecurity, and biological stability. The “state-of-the-art” antimicrobial modes of Ns-AMPs, including controlled release of AMPs under a specific environment or intrinsic antimicrobial properties of Ns-AMPs, are also explicated. Finally, the perspectives and conclusions of the current research in this field are also summarized.

scholarly journals Pharmacological Inhibition of the ClpXP Protease Increases Bacterial Susceptibility to Host Cathelicidin Antimicrobial Peptides and Cell Envelope-Active Antibiotics

2012 ◽  
Vol 56 (4) ◽  
pp. 1854-1861 ◽  
Author(s):  
Shauna M. McGillivray ◽  
Dan N. Tran ◽  
Nitya S. Ramadoss ◽  
John N. Alumasa ◽  
Cheryl Y. Okumura ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Pathogenic Bacteria ◽  
Therapeutic Strategy ◽  
Cell Envelope ◽  
Bacterial Species ◽  
Drug Resistant ◽  
Host Defenses ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACTThe ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action inBacillus anthracisandStaphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, inB. anthracisand drug-resistant strains ofS. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.

scholarly journals Daptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Truc T. Tran ◽  
Diana Panesso ◽  
Nagendra N. Mishra ◽  
Eugenia Mileykovskaya ◽  
Ziqianq Guan ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cell Surface ◽  
Antimicrobial Peptides ◽  
Enterococcus Faecalis ◽  
Cell Envelope ◽  
Multidrug Resistant ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Cardiolipin Synthase

ABSTRACT Treatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant enterococci (VRE). However, the clinical use of DAP against VRE is threatened by emergence of resistance during therapy, but the mechanisms leading to DAP resistance are not fully understood. The mechanism of action of DAP involves interactions with the cell membrane in a calcium-dependent manner, mainly at the level of the bacterial septum. Previously, we demonstrated that development of DAP resistance in vancomycin-resistant Enterococcus faecalis is associated with mutations in genes encoding proteins with two main functions, (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase). In this work, we show that these VRE can resist DAP-elicited cell membrane damage by diverting the antibiotic away from its principal target (division septum) to other distinct cell membrane regions. DAP septal diversion by DAP-resistant E. faecalis is mediated by initial redistribution of cell membrane cardiolipin-rich microdomains associated with a single amino acid deletion within the transmembrane protein LiaF (a member of a three-component regulatory system [LiaFSR] involved in cell envelope homeostasis). Full expression of DAP resistance requires additional mutations in enzymes (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase) that alter cell membrane phospholipid content. Our findings describe a novel mechanism of bacterial resistance to cationic antimicrobial peptides. IMPORTANCE The emergence of antibiotic resistance in bacterial pathogens is a threat to public health. Understanding the mechanisms of resistance is of crucial importance to develop new strategies to combat multidrug-resistant microorganisms. Vancomycin-resistant enterococci (VRE) are one of the most recalcitrant hospital-associated pathogens against which new therapies are urgently needed. Daptomycin (DAP) is a calcium-decorated antimicrobial lipopeptide whose target is the bacterial cell membrane. A current paradigm suggests that Gram-positive bacteria become resistant to cationic antimicrobial peptides via an electrostatic repulsion of the antibiotic molecule from a more positively charged cell surface. In this work, we provide evidence that VRE use a novel strategy to avoid DAP-elicited killing. Instead of “repelling” the antibiotic from the cell surface, VRE diverts the antibiotic molecule from the septum and “traps” it in distinct membrane regions. We provide genetic and biochemical bases responsible for the mechanism of resistance and disclose new targets for potential antimicrobial development.

scholarly journals Synergy pattern of short cationic antimicrobial peptides against multidrug-resistant Pseudomonas aeruginosa

2019 ◽  
Author(s):  
Serge Ruden ◽  
Annika Rieder ◽  
Thomas Schwartz ◽  
Ralf Mikut ◽  
Kai Hilpert
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Peptides ◽  
Pathogenic Bacteria ◽  
Synergistic Effects ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Multi Drug Resistance ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Conventional Antibiotics

AbstractWith the rise of various multi-drug resistance pathogenic bacteria, worldwide health care is under pressure to respond. Conventional antibiotics are failing and the development of novel classes or alternative strategies is a major priority. Antimicrobial peptides (AMPs) can not only kill multi-drug resistant bacteria, but also can be used synergistically with conventional antibiotics. We selected 30 short AMPs from different origins and measured their synergy in combination with Polymyxin B, Piperacillin, Ceftazidime, Cefepime, Meropenem, Imipenem, Tetracycline, Erythromycin, Kanamycin, Tobramycin, Amikacin, Gentamycin, and Ciprofloxacin. In total 403 unique combinations were tested against a multi-drug resistant Pseudomonas aeruginosa isolate (PA910). As a measure of the synergistic effects, fractional inhibitory concentrations (FICs) were determined using microdilution assays with FICs ranges between 0.25 and 2. A high number of combinations between peptides and Polymyxin B, Erythromycin and Tetracycline were found to be synergistic. Novel variants of Indolicidin also showed a high frequency in synergist interaction.

Antimicrobial Peptides and their Multiple Effects at Sub-Inhibitory Concentrations

2020 ◽  
Vol 20 (14) ◽  
pp. 1264-1273 ◽  
Author(s):  
Bruno Casciaro ◽  
Floriana Cappiello ◽  
Walter Verrusio ◽  
Mauro Cacciafesta ◽  
Maria Luisa Mangoni
Keyword(s):  
Antimicrobial Peptides ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Lead Compounds ◽  
Bacterial Pathogenicity ◽  
Growth Inhibitory ◽  
Resistant Strains ◽  
Conventional Antibiotics

The frequent occurrence of multidrug-resistant strains to conventional antimicrobials has led to a clear decline in antibiotic therapies. Therefore, new molecules with different mechanisms of action are extremely necessary. Due to their unique properties, antimicrobial peptides (AMPs) represent a valid alternative to conventional antibiotics and many of them have been characterized for their activity and cytotoxicity. However, the effects that these peptides cause at concentrations below the minimum growth inhibitory concentration (MIC) have yet to be fully analyzed along with the underlying molecular mechanism. In this mini-review, the ability of AMPs to synergize with different antibiotic classes or different natural compounds is examined. Furthermore, data on microbial resistance induction are reported to highlight the importance of antibiotic resistance in the fight against infections. Finally, the effects that sub-MIC levels of AMPs can have on the bacterial pathogenicity are summarized while showing how signaling pathways can be valid therapeutic targets for the treatment of infectious diseases. All these aspects support the high potential of AMPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities.

Biochemical Composition, Antibacterial and Anti-Biofilm Activities of Indian Medicinal Plants

2020 ◽  
Vol 18 ◽  
Author(s):  
Mulugeta Mulat ◽  
Fazlurrahman Khan ◽  
Archana Pandita
Keyword(s):  
Antibacterial Activity ◽  
Medicinal Plants ◽  
Pathogenic Bacteria ◽  
Chemical Constituents ◽  
Multidrug Resistant ◽  
Chloroform Extract ◽  
Acetone Extract ◽  
Biologically Active ◽  
Ocimum Sanctum ◽  
Agar Disc

Background: Medicinal plants have been used for treatments of various health ailments and the practices as a remedial back to thousands of years. Currently, plant-derived compounds used as alternative ways of treatment for multidrug-resistant pathogens. Objective: In the present study, various parts of six medical plants such as Solanum nigrum, Azadirachta indica, Vitex negundo, Mentha arvensis, Gloriosa superba, and Ocimum sanctum were extracted for obtaining biological active constituents. Methods: Soxhlet method of extraction was used for obtaining crude extracts. Agar disc diffusion and 96-well plate spectroscopic reading were used to detect the extract’s antibacterial and antibiofilm properties. Results: The obtained extracts were tested for antimicrobial and antibiofilm properties at 25 mg/mL concentrations. Maximum antibacterial activity was observed in O. sanctum chloroform extract (TUCE) against Staphylococcus aureus (24.33±1.52 mm), S. nigrum acetone extract (MAAC) against Salmonella Typhimurium (12.6 ± 1.5 mm) and Pseudomonas aeruginosa (15.0 ±2.0 mm). Only TUCE exhibited antibacterial activity at least a minimum inhibitory concentration of 0.781 mg/mL. Better antibiofilm activities were also exhibited by petroleum extracts of G. superba (KAPE) and S. nigrum (MAPE) against Escherichia coli, S. Typhimurium, P. aeruginosa and S. aureus. Moreover, S. nigrum acetone extract (MAAC) and O. sanctum chloroform extract (TUCE) were showed anti-swarming activity with a reduction of motility 56.3% against P. aeruginosa and 37.2% against S. aureus. MAAC also inhibits Las A activity (63.3% reduction) in P. aeruginosa. Conclusion: Extracts of TUCE, MAAC, MAPE, and KAPE were exhibited antibacterial and antibiofilm properties against the Gram-positive and Gram-negative pathogenic bacteria. GCMS identified chemical constituents are responsible for being biologically active.

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