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.

scholarly journals Discovery and Optimization of Inhibitors for the Pup Proteasome System in Mycobacterium tuberculosis

2019 ◽  
Author(s):  
Guido V. Janssen ◽  
Susan Zhang ◽  
Remco Merkx ◽  
Christa Schiesswohl ◽  
Champak Chatterjee ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Fluorogenic Substrate ◽  
Lead Compounds ◽  
Competitive Inhibitors ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Global Health Problem

AbstractTuberculosis is a global health problem with the existence and spreading of multidrug resistant and extensive drug resistant strains. The development of new drugs for tuberculosis that inhibit different activities than the current drugs is thus urgent. The prokaryotic ubiquitin like protein proteasome system is an attractive target for the development of new drugs. Using a Pup-based fluorogenic substrate, we screened for inhibitors of Dop, a depupylase, and identified I-OMe-Tyrphostin AG538 (1) and Tyrphostin AG53 (2). The hits were validated and determined to be fast reversible non-ATP competitive inhibitors. The SAR was established by testing 27 synthesized analogs of 1 and 2. Several of the synthesized compounds also inhibited the depupylation of a native substrate, FabD∼Pup. Importantly, the pupylation and depupylation activities of PafA, the sole Pup ligase in M. tuberculosis, was also inhibited by some of these compounds. With the identification of the first described lead compounds for Dop and PafA inhibition, this study shows that high throughput screening can be a successful strategy for this purpose.

Antituberculosis activities of clofazimine and its new analogs B4154 and B4157.

1996 ◽  
Vol 40 (3) ◽  
pp. 633-636 ◽  
Author(s):  
V M Reddy ◽  
G Nadadhur ◽  
D Daneluzzi ◽  
J F O'Sullivan ◽  
P R Gangadharam
Keyword(s):  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drugs ◽  
Resistant Tuberculosis ◽  
Chemotherapeutic Activity ◽  
Resistant Strains ◽  
Intracellular Activities ◽  
Moderate Resistance ◽  
Drug Resistant Strains

In our efforts to develop new drugs for the treatment of tuberculosis, especially that caused by multidrug-resistant strains, we investigated clofazimine (CFM) and two of its analogs, B4154 and B4157, for their antituberculosis activities. Twenty M. tuberculosis strains were tested, including 16 drug-resistant strains (strains resistant to one or more antituberculosis drugs), for their susceptibilities to these three agents. All of the strains were found to be susceptible to B4154 and B4157, and one strain showed moderate resistance to CFM. The MICs of B4154, B4157, and CFM at which 90% of strains were inhibited were 0.25, 0.12, and < or = 1.0 microgram/ml, respectively. The intracellular activities of CFM and B4157 were superior to that of B4154. The chemotherapeutic activities of the three compounds were evaluated in C57BL/6 mice. At a dose of 20 mg/kg of body weight, the activity of CFM was slightly superior to that of B4157; however, both compounds prevented mortality and caused a significant reduction in the numbers of CFU in the lungs and spleens. The animals treated with B4157 showed less pigmentation than animals treated with CFM. The chemotherapeutic activity of CFM was comparable to those of rifampin and isoniazid. Complete susceptibility of multidrug-resistant strains to CFM and B4157 and the therapeutic efficacies of these compounds against mouse tuberculosis make these drugs attractive agents for the treatment of drug-resistant tuberculosis.

Antimicrobial peptides: an overview of a promising class of therapeutics

2007 ◽  
Vol 2 (1) ◽  
pp. 1-33 ◽  
Author(s):  
Andrea Giuliani ◽  
Giovanna Pirri ◽  
Silvia Nicoletto
Keyword(s):  
Antimicrobial Peptides ◽  
Multidrug Resistant ◽  
Innate Immune ◽  
Resistant Bacteria ◽  
Yeast Fungi ◽  
Wide Range ◽  
New Development ◽  
Catheter Site ◽  
Conventional Antibiotics

AbstractAntibiotic resistance is increasing at a rate that far exceeds the pace of new development of drugs. Antimicrobial peptides, both synthetic and from natural sources, have raised interest as pathogens become resistant against conventional antibiotics. Indeed, one of the major strengths of this class of molecules is their ability to kill multidrug-resistant bacteria. Antimicrobial peptides are relatively small (6 to 100 aminoacids), amphipathic molecules of variable length, sequence and structure with activity against a wide range of microorganisms including bacteria, protozoa, yeast, fungi, viruses and even tumor cells. They usually act through relatively non-specific mechanisms resulting in membranolytic activity but they can also stimulate the innate immune response. Several peptides have already entered pre-clinical and clinical trials for the treatment of catheter site infections, cystic fibrosis, acne, wound healing and patients undergoing stem cell transplantation. We review the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization.

Increasing of the Aminoglicosyde Antibiotic Activity Against a Multidrug-Resistant E. coli by Turnera ulmifolia L. and Chlorpromazine

2009 ◽  
Vol 11 (4) ◽  
pp. 332-335 ◽  
Author(s):  
Henrique D. M. Coutinho ◽  
José G. M. Costa ◽  
Edeltrudes O. Lima ◽  
Vivyanne S. Falcão-Silva ◽  
José P. Siqueira-Júnior
Keyword(s):  
Bacterial Resistance ◽  
Inhibitory Concentration ◽  
Ethanol Extract ◽  
Multidrug Resistant ◽  
Coli Strain ◽  
Minimal Bactericidal Concentration ◽  
Efflux System ◽  
E Coli ◽  
Turnera Ulmifolia ◽  
Conventional Antibiotics

In this study, an ethanol extract of Turnera ulmifolia L. (EETU) and chlorpromazine (CPZ) were tested for their antimicrobial activity alone or in combination with conventional antibiotics against two strains of Escherichia coli (E. coli). The growth of neither E. coli strain was inhibited by the extract. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration values were ≥1 mg/ml for both the strains of E. coli. However, the extract did increase the antimicrobial effects of amikacin, neomycin, and tobramycin. A similar effect of CPZ on amikacin, kanamycin, and tobramycin indicated the involvement of an efflux system in the resistance to these aminoglycosides. Results suggest that extracts from T. ulmifolia could be used as a plant-derived natural product with resistance-modifying activity, constituting a new weapon against bacterial resistance to antibiotics.

Anti-mycobacterial Constituents from Medicinal Plants; A Review

2021 ◽  
Vol 21 ◽  
Author(s):  
Nandan Sarkar ◽  
Yadu Nandan Dey ◽  
Dharmendra Kumar ◽  
Mogana R
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Medicinal Plants ◽  
Development Process ◽  
Multidrug Resistant ◽  
Review Article ◽  
New Drugs ◽  
Drug Resistant ◽  
Drug Discovery And Development ◽  
Resistant Strains ◽  
Drug Resistant Strains

: Effective treatment of tuberculosis has been hindered by the emergence of drug-resistant strains of Mycobacterium therapeutic facilities tuberculosis. With the global resurgence of tuberculosis with the development of multidrug-resistant cases, there is a call for the development of new drugs to combat these diseases. Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology, and continued to play a significant role in the drug discovery and development process. This review article depicts the various potential plant extracts as well as plant-derived phytoconstituents against the H37rv, the most persistent strains of Mycobacterium tuberculosis and its multidrug strains.

scholarly journals Two Hits Are Better than One: Membrane-Active and DNA Binding-Related Double-Action Mechanism of NK-18, a Novel Antimicrobial Peptide Derived from Mammalian NK-Lysin

2012 ◽  
Vol 57 (1) ◽  
pp. 220-228 ◽  
Author(s):  
Jiexi Yan ◽  
Kairong Wang ◽  
Wen Dang ◽  
Ru Chen ◽  
Junqiu Xie ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Cytotoxic T Cells ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Content Type ◽  
New Strategy ◽  
Conventional Antibiotics ◽  
Double Targets

ABSTRACTThe extensive use and misuse of antibiotics in medicine result in the emergence of multidrug-resistant bacteria, creating an urgent need for the development of new chemotherapeutic agents. Nowadays, antimicrobial peptides are widely recognized as a class of promising candidates with activity against multidrug-resistant bacteria. NK-18 is a truncated peptide derived from NK-Lysin, an effector of cytotoxic T cells and natural killer cells. In this study, we studied the antibacterial mechanism of action of NK-18. The results revealed that NK-18 has potent antibacterial activity againstEscherichia coliandStaphylococcus aureus. According to our findings, NK-18 is membrane active and its target of action is not only the bacterial membrane but also the DNA in the cytoplasm. The double targets of NK-18 make it difficult for bacteria to generate resistance, which may present a new strategy to defend against multidrug-resistant bacteria and provide a new lead in the design of potent antimicrobial peptides with therapeutic application in the presence of increasing resistance to conventional antibiotics.

scholarly journals Rifabutin and Furazolidone Could Be the Candidates of the Rescue Regimen for Antibiotic-Resistant H. pylori in Korea

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Youn I Choi ◽  
Sang-Ho Jeong ◽  
Jun-Won Chung ◽  
Dong Kyun Park ◽  
Kyoung Oh Kim ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Medical Center ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Antibiotic Resistant ◽  
Asan Medical ◽  
Resistant Strains ◽  
H Pylori ◽  
Resistance Rates ◽  
Reference Strains

Background/Aim. In Korea, the rate of Helicobacter pylori (H. pylori) eradication has declined steadily as a result of increasing resistance to antibiotics, especially dual resistance to clarithromycin and metronidazole. However, microbiological culture data on drug-resistant H. pylori is lacking. This study evaluated the antimicrobial efficacy of candidate antibiotics against resistant H. pylori strains. Methods. After retrospectively reviewing the data from the Helicobacter Registry in Gil Medical Center (GMC) and Asan Medical Center (AMC), along with 4 reference strains, we selected the 31 single- or multidrug-resistant strains. The susceptibility of the H. pylori strains to seven antibiotics (clarithromycin, metronidazole, levofloxacin, amoxicillin, tetracycline, rifabutin, and furazolidone) and minimum inhibitory concentration were tested using the broth microdilution technique. Results. Among 31 antibiotic resistance strains for H. pylori, there were no strains resistant to rifabutin or furazolidone, which had MICs of <0.008 and 0.5 μg/mL, respectively. Only one tetracycline-resistant strain was found (MIC < 2 μg/mL). Amoxicillin and levofloxacin were relatively less effective against the H. pylori strains compared to rifabutin or furazolidone (resistance rates 22.6%, 1.9%, respectively). Tetracycline showed the relatively low resistance rates (3.2%) for H. pylori strains. Conclusions. Therefore, along with tetracycline which has already been used as a component for second-line eradication regimen for Helicobacter, rifabutin and furazolidone, alone or in combination, could be used to eradicate antibiotic-resistant H. pylori strains where drug-resistant Helicobacter spp. are increasing.

scholarly journals Effects of associations of tannins from Anacardium occidentale and Anadenanthera colubrina with cephalosporin against bovine Staphylococcus aureus isolates

2018 ◽  
Vol 85 (0) ◽  
Author(s):  
Andréia Vieira Pereira ◽  
Marcelo Biondaro Góis ◽  
Tatiane Kelly Barbosa Azevêdo ◽  
Fabiana Nabarro Ferraz ◽  
Suellen Laís Vicentino Vieira ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Drug Resistance ◽  
Inhibitory Concentration ◽  
Antibacterial Effect ◽  
Mechanisms Of Action ◽  
Anacardium Occidentale ◽  
Distilled Water ◽  
Conventional Antibiotics

ABSTRACT: The association of natural compounds isolated from medicinal plants with conventional antibiotics, both with similar mechanisms of action, have become a viable alternative strategy to overcome the problem of drug resistance. This study aimed to evaluate the in vitro antimicrobial activity of tannic substances present in the bark of Anacardium occidentale and Anadenanthera colubrina against samples of Staphylococcus aureus when in combination with cephalexin. These combinations were evaluated by determining the minimum inhibitory concentration (MIC). For this purpose, tannins and cephalexin were serially dissolved in distilled water at concentrations ranging from 0.976 mg/mL to 500 mg/mL and 2 mg/mL to 512 mg/mL, respectively. When combined, the compounds inhibited S. aureus growth forming halos ranging from 0.9 to 46 mm with an MIC of 7.8 mg/mL (tannins) and 4 µg/mL (cephalexin). The resulting effect of the combination of natural and synthetic substances with similar mechanisms of action presented better results than when tested alone. Thus, the conclusion is that both the tannins and cephalexin had their antimicrobial action enhanced when used in combination, enabling the use of lower concentrations while maintaining their antibacterial effect against strains of S. aureus.

scholarly journals Generating Ampicillin-Level Antimicrobial Peptides with Activity-Aware Generative Adversarial Networks

2020 ◽  
Author(s):  
Andrejs Tucs ◽  
Duy Phuoc Tran ◽  
Akiko Yumoto ◽  
Yoshihiro Ito ◽  
Takanori Uzawa ◽  
...  
Keyword(s):  
Minimum Inhibitory Concentration ◽  
Antimicrobial Peptides ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Generative Models ◽  
Generative Adversarial Networks ◽  
Potential Solution ◽  
Active Peptides ◽  
Adversarial Networks ◽  
Physicochemical Descriptors

<p>Antimicrobial peptides are a potential solution to the threat of multidrug-resistant bacterial pathogens. Recently, deep generative models including generative adversarial networks (GANs) have been shown to be capable of designing new antimicrobial peptides. Intuitively, a GAN controls the probability distribution of generated sequences to cover active peptides as much as possible. This paper presents a peptide-specialized model called PepGAN that takes the balance between covering active peptides and</p><p>dodging non-active peptides. As a result, PepGAN has superior statistical fidelity with respect to physicochemical descriptors including charge, hydrophobicity and weight. Top six peptides were synthesized and one of them was confirmed to be highly antimicrobial. The minimum inhibitory concentration was 3.1μg/mL, indicating that the peptide is twice as strong as ampicillin.</p>

scholarly journals Imcroporin, a New Cationic Antimicrobial Peptide from the Venom of the Scorpion Isometrus maculates

2009 ◽  
Vol 53 (8) ◽  
pp. 3472-3477 ◽  
Author(s):  
Zhenhuan Zhao ◽  
Yibao Ma ◽  
Chao Dai ◽  
Ruiming Zhao ◽  
SongRyong Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Lead Compound ◽  
Cationic Antimicrobial Peptide ◽  
Antibiotic Resistant ◽  
Multidrug Resistant Pathogens ◽  
Conventional Antibiotics

ABSTRACT The pace of resistance against antibiotics almost exceeds that of the development of new drugs. As many bacteria have become resistant to conventional antibiotics, new drugs or drug resources are badly needed to combat antibiotic-resistant pathogens, like methicillin-resistant Staphylococcus aureus (MRSA). Antimicrobial peptides, rich sources existing in nature, are able to effectively kill multidrug-resistant pathogens. Here, imcroporin, a new antimicrobial peptide, was screened and isolated from the cDNA library of the venomous gland of Isometrus maculates. The MIC of imcroporin against MRSA was 50 μg/ml, 8-fold lower than that of cefotaxime and 40-fold lower than that of penicillin. Imcroporin killed bacteria rapidly in vitro, inhibited bacterial growth, and cured infected mice. These results revealed that imcroporin could be considered a potential anti-infective drug or lead compound, especially for treating antibiotic-resistant pathogens.

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