scholarly journals Bacteria primed by antimicrobial peptides develop tolerance and persist

2019 ◽  
Author(s):  
Alexandro Rodríguez-Rojas ◽  
Desiree Y. Baeder ◽  
Paul Johnston ◽  
Roland R. Regoes ◽  
Jens Rolff
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Peptides ◽  
Adaptive Response ◽  
Innate Immune ◽  
New Drugs ◽  
Bacterial Survival ◽  
Population Dynamic Model ◽  
Evolution Of Resistance ◽  
Sublethal Doses ◽  
High Concentrations

SUMMARYAntimicrobial peptides (AMPs) are key components of innate immune defenses. Because of the antibiotic crisis, AMPs have also come into focus as new drugs. Here, we explore whether prior exposure to sublethal doses of AMPs increases bacterial survival and abets the evolution of resistance. We show that Escherichia coli primed by sublethal doses of AMPs develop tolerance and increase persistence by producing curli or colanic acid. We develop a population dynamic model that predicts that priming delays the clearance of infections and fuels the evolution of resistance. The effects we describe should apply to many AMPs and other drugs that target the cell surface. The optimal strategy to tackle tolerant or persistent cells requires high concentrations of AMPs and fast and long-lasting expression. Our findings also offer a new understanding of non-inherited drug resistance as an adaptive response and could lead to measures that slow the evolution of resistance.

scholarly journals Bacteria primed by antimicrobial peptides develop tolerance and persist

2021 ◽  
Vol 17 (3) ◽  
pp. e1009443
Author(s):  
Alexandro Rodríguez-Rojas ◽  
Desiree Y. Baeder ◽  
Paul Johnston ◽  
Roland R. Regoes ◽  
Jens Rolff
Keyword(s):  
Antimicrobial Peptides ◽  
Adaptive Response ◽  
Biofilm Formation ◽  
Innate Immune ◽  
New Drugs ◽  
Bacterial Survival ◽  
Population Dynamic Model ◽  
Evolution Of Resistance ◽  
High Concentrations ◽  
Lethal Doses

Antimicrobial peptides (AMPs) are key components of innate immune defenses. Because of the antibiotic crisis, AMPs have also come into focus as new drugs. Here, we explore whether prior exposure to sub-lethal doses of AMPs increases bacterial survival and abets the evolution of resistance. We show that Escherichia coli primed by sub-lethal doses of AMPs develop tolerance and increase persistence by producing curli or colanic acid, responses linked to biofilm formation. We develop a population dynamic model that predicts that priming delays the clearance of infections and fuels the evolution of resistance. The effects we describe should apply to many AMPs and other drugs that target the cell surface. The optimal strategy to tackle tolerant or persistent cells requires high concentrations of AMPs and fast and long-lasting expression. Our findings also offer a new understanding of non-inherited drug resistance as an adaptive response and could lead to measures that slow the evolution of resistance.

Inactivation of Escherichia coli in Milk by High-Hydrostatic-Pressure Treatment in Combination with Antimicrobial Peptides

1999 ◽  
Vol 62 (11) ◽  
pp. 1248-1254 ◽  
Author(s):  
CRISTINA GARCÍA-GRAELLS ◽  
BARBARA MASSCHALCK ◽  
CHRIS W. MICHIELS
Keyword(s):  
Escherichia Coli ◽  
Hydrostatic Pressure ◽  
Antimicrobial Peptides ◽  
High Hydrostatic Pressure ◽  
Skim Milk ◽  
Substantial Improvement ◽  
Pressure Treatment ◽  
Different Temperatures ◽  
Resistant Mutants ◽  
High Concentrations

We studied the inactivation in milk of four Escherichia coli strains (MG1655 and three pressure-resistant mutants isolated from MG1655) by high hydrostatic pressure, alone or in combination with the natural antimicrobial peptides lysozyme and nisin and at different temperatures (10 to 50°C). Compared with that of phosphate buffer, the complex physicochemical environment of milk exerted a strong protective effect on E. coli MG1655 against high-hydrostatic-pressure inactivation, reducing inactivation from 7 logs at 400 MPa to only 3 logs at 700 MPa in 15 min at 20°C. An increase in lethality was achieved by addition of high concentrations of lysozyme (400 μg/ml) and nisin (400 IU/ml) to the milk before pressure treatment. The additional reduction amounted maximally to 3 logs in skim milk at 550 MPa but was strain dependent and significantly reduced in 1.55% fat and whole milk. An increase of the process temperature to 50°C also enhanced inactivation, particularly for the parental strain, but even in the presence of lysozyme and nisin, a 15-min treatment at 550 MPa and 50°C in skim milk allowed decimal reductions of only 4.5 to 6.9 for the pressure-resistant mutants. A substantial improvement of inactivation efficiency at ambient temperature was achieved by application of consecutive, short pressure treatments interrupted by brief decompressions. Interestingly, this pulsed-pressure treatment enhanced the sensitivity of the cells not only to high pressure but also to the action of lysozyme and nisin.

scholarly journals Identification of Mycobacterium avium genes associated with resistance to host antimicrobial peptides

2014 ◽  
Vol 63 (7) ◽  
pp. 923-930 ◽  
Author(s):  
Nima Motamedi ◽  
Lia Danelishvili ◽  
Luiz E. Bermudez
Keyword(s):  
Antimicrobial Peptides ◽  
Mycobacterium Avium ◽  
Great Majority ◽  
Polymyxin B ◽  
Innate Immune ◽  
Immune Defence ◽  
Gastrointestinal Mucosa ◽  
Gene Encoding ◽  
High Concentrations ◽  
Macrophage Killing

Antimicrobial peptides are an important component of the innate immune defence. Mycobacterium avium subsp. hominissuis (M. avium) is an organism that establishes contact with the respiratory and gastrointestinal mucosa as a necessary step for infection. M. avium is resistant to high concentrations of polymyxin B, a surrogate for antimicrobial peptides. To determine gene-encoding proteins that are associated with this resistance, we screened a transposon library of M. avium strain 104 for susceptibility to polymyxin B. Ten susceptible mutants were identified and the inactivated genes sequenced. The great majority of the genes were related to cell wall synthesis and permeability. The mutants were then examined for their ability to enter macrophages and to survive macrophage killing. Three clones among the mutants had impaired uptake by macrophages compared with the WT strain, and all ten clones were attenuated in macrophages. The mutants were also shown to be susceptible to cathelicidin (LL-37), in contrast to the WT bacterium. All but one of the mutants were significantly attenuated in mice. In conclusion, this study indicated that the M. avium envelope is the primary defence against host antimicrobial peptides.

scholarly journals Control of Bacterial Persister Cells by Trp/Arg-Containing Antimicrobial Peptides

2011 ◽  
Vol 77 (14) ◽  
pp. 4878-4885 ◽  
Author(s):  
Xi Chen ◽  
Mi Zhang ◽  
Chunhui Zhou ◽  
Neville R. Kallenbach ◽  
Dacheng Ren
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Peptides ◽  
Future Development ◽  
Bacterial Population ◽  
Lower Threshold ◽  
Chronic Infections ◽  
Persister Cells ◽  
Normal Cells ◽  
Content Type ◽  
High Concentrations

ABSTRACTPersister cells are dormant phenotypic variants inherent in a bacterial population. They play important roles in chronic infections and present great challenges to therapy due to extremely enhanced tolerance to antibiotics compared to that of normal cells of the same genotype. In this study, we report that cationic membrane-penetrating peptides containing various numbers of arginine and tryptophan repeats are effective in killing persister cells ofEscherichia coliHM22, a hyper-persister producer. The activities of three linear peptides [(RW)n-NH2, wherenis 2, 3, or 4] and a dendrimeric peptide, (RW)4D, in killing bacterial persisters were compared. Although the dendrimeric peptide (RW)4Drequires a lower threshold to kill planktonic persisters, octameric peptide (RW)4-NH2is the most effective against planktonic persister cells at high concentrations. For example, treatment with 80 μM (RW)4-NH2for 60 min led to a 99.7% reduction in the number of viable persister cells. The viability of persister cells residing in surface-attached biofilms was also significantly reduced by (RW)4-NH2and (RW)4D. These two peptides were also found to significantly enhance the susceptibility of biofilm cells to ofloxacin. The potency of (RW)4-NH2was further marked by its ability to disperse and kill preformed biofilms harboring high percentages of persister cells. Interestingly, approximately 70% of the dispersed cells were found to have lost their intrinsic tolerance and become susceptible to ampicillin if not killed directly by this peptide. These results are helpful for better understanding the activities of these peptides and may aid in future development of more effective therapies of chronic infections.

scholarly journals Differential Chromosome- and Plasmid-Borne Resistance of Escherichia coli hfq Mutants to High Concentrations of Various Antibiotics

2021 ◽  
Vol 22 (16) ◽  
pp. 8886
Author(s):  
Lidia Gaffke ◽  
Krzysztof Kubiak ◽  
Zuzanna Cyske ◽  
Grzegorz Węgrzyn
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Terminal Region ◽  
Bacterial Survival ◽  
Null Mutant ◽  
Resistance Marker ◽  
Plasmid Copy ◽  
Rna Chaperone ◽  
High Concentrations ◽  
High Doses

The Hfq protein is a bacterial RNA chaperone, involved in many molecular interactions, including control of actions of various small RNA regulatory molecules. We found that the presence of Hfq was required for survival of plasmid-containing Escherichia coli cells against high concentrations of chloramphenicol (plasmid p27cmr), tetracycline (pSC101, pBR322) and ampicillin (pBR322), as hfq+ strains were more resistant to these antibiotics than the hfq-null mutant. In striking contrast, production of Hfq resulted in low resistance to high concentrations of kanamycin when the antibiotic-resistance marker was chromosome-borne, with deletion of hfq resulting in increasing bacterial survival. These results were observed both in solid and liquid medium, suggesting that antibiotic resistance is an intrinsic feature of these strains rather than a consequence of adaptation. Despite its major role as RNA chaperone, which also affects mRNA stability, Hfq was not found to significantly affect kan and tet mRNAs turnover. Nevertheless, kan mRNA steady-state levels were higher in the hfq-null mutant compared to the hfq+ strain, suggesting that Hfq can act as a repressor of kan expression.This observation does correlate with the enhanced resistance to high levels of kanamycin observed in the hfq-null mutant. Furthermore, dependency on Hfq for resistance to high doses of tetracycline was found to depend on plasmid copy number, which was only observed when the resistance marker was expressed from a low copy plasmid (pSC101) but not from a medium copy plasmid (pBR322). This suggests that Hfq may influence survival against high doses of antibiotics through mechanisms that remain to be determined. Studies with pBR322Δrom may also suggest an interplay between Hfq and Rom in the regulation of ColE1-like plasmid replication. Results of experiments with a mutant devoid of the part of the hfq gene coding for the C-terminal region of Hfq suggested that this region, as well as the N-terminal region, may be involved in the regulation of expression of antibiotic resistance in E. coli independently.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

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 Proteomic response of Escherichia coli to a membrane lytic and iron chelating truncated Amaranthus tricolor defensin

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tessa B. Moyer ◽  
Ashleigh L. Purvis ◽  
Andrew J. Wommack ◽  
Leslie M. Hicks
Keyword(s):  
Escherichia Coli ◽  
Antibacterial Activity ◽  
Antimicrobial Peptides ◽  
Mechanism Of Action ◽  
Gram Negative Bacteria ◽  
Amaranthus Tricolor ◽  
Core Motif ◽  
Gram Negative ◽  
E Coli ◽  
Membrane Lysis

Abstract Background Plant defensins are a broadly distributed family of antimicrobial peptides which have been primarily studied for agriculturally relevant antifungal activity. Recent studies have probed defensins against Gram-negative bacteria revealing evidence for multiple mechanisms of action including membrane lysis and ribosomal inhibition. Herein, a truncated synthetic analog containing the γ-core motif of Amaranthus tricolor DEF2 (Atr-DEF2) reveals Gram-negative antibacterial activity and its mechanism of action is probed via proteomics, outer membrane permeability studies, and iron reduction/chelation assays. Results Atr-DEF2(G39-C54) demonstrated activity against two Gram-negative human bacterial pathogens, Escherichia coli and Klebsiella pneumoniae. Quantitative proteomics revealed changes in the E. coli proteome in response to treatment of sub-lethal concentrations of the truncated defensin, including bacterial outer membrane (OM) and iron acquisition/processing related proteins. Modification of OM charge is a common response of Gram-negative bacteria to membrane lytic antimicrobial peptides (AMPs) to reduce electrostatic interactions, and this mechanism of action was confirmed for Atr-DEF2(G39-C54) via an N-phenylnaphthalen-1-amine uptake assay. Additionally, in vitro assays confirmed the capacity of Atr-DEF2(G39-C54) to reduce Fe3+ and chelate Fe2+ at cell culture relevant concentrations, thus limiting the availability of essential enzymatic cofactors. Conclusions This study highlights the utility of plant defensin γ-core motif synthetic analogs for characterization of novel defensin activity. Proteomic changes in E. coli after treatment with Atr-DEF2(G39-C54) supported the hypothesis that membrane lysis is an important component of γ-core motif mediated antibacterial activity but also emphasized that other properties, such as metal sequestration, may contribute to a multifaceted mechanism of action.

scholarly journals Structure and expression of the alkA gene of Escherichia coli involved in adaptive response to alkylating agents.

1984 ◽  
Vol 259 (22) ◽  
pp. 13730-13736 ◽  
Author(s):  
Y Nakabeppu ◽  
T Miyata ◽  
H Kondo ◽  
S Iwanaga ◽  
M Sekiguchi
Keyword(s):  
Escherichia Coli ◽  
Adaptive Response ◽  
Alkylating Agents

scholarly journals Autophagy—A Story of Bacteria Interfering with the Host Cell Degradation Machinery

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 110
Author(s):  
Anna K. Riebisch ◽  
Sabrina Mühlen ◽  
Yan Yan Beer ◽  
Ingo Schmitz
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Listeria Monocytogenes ◽  
Salmonella Typhimurium ◽  
Innate Immune ◽  
Intracellular Pathogens ◽  
Response Mechanism ◽  
Pathogenic Escherichia Coli

Autophagy is a highly conserved and fundamental cellular process to maintain cellular homeostasis through recycling of defective organelles or proteins. In a response to intracellular pathogens, autophagy further acts as an innate immune response mechanism to eliminate pathogens. This review will discuss recent findings on autophagy as a reaction to intracellular pathogens, such as Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Staphylococcus aureus, and pathogenic Escherichia coli. Interestingly, while some of these bacteria have developed methods to use autophagy for their own benefit within the cell, others have developed fascinating mechanisms to evade recognition, to subvert the autophagic pathway, or to escape from autophagy.

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