Novel Peptides Targeting the β-Clamp Rapidly Kill Planktonic and Biofilm Staphylococcus epidermidis Both in vitro and in vivo

Antimicrobial resistance is an increasing threat to global health and challenges the way we treat infections. Peptides containing the PCNA interacting motif APIM (APIM-peptides) were recently shown to bind to the bacterial PCNA homolog, the beta (β)-clamp, and to have both antibacterial and anti-mutagenic activities. In this study we explore the antibacterial effects of these peptides on Staphylococcus epidermidis, a bacterial species commonly found in prosthetic joint infections (PJI). Drug-resistant bacterial isolates from PJIs often lead to difficult-to-treat chronic infections. We show that APIM-peptides have a rapid bactericidal effect which when used at sublethal levels also increase the efficacy of gentamicin. In addition, APIM-peptides reduce development and eliminate already existing S. epidermidis biofilm. To study the potential use of APIM-peptides to prevent PJI, we used an in vivo bone graft model in rats where APIM-peptide, gentamicin, or a combination of the two was added to cement. The bone grafts containing cement with the combination was more effective than cement containing only gentamicin, which is the current standard of care. In summary, these results suggest that APIM-peptides can be a promising new drug candidate for anti-infective implant materials to use in the fight against resistant bacteria and chronic PJI.

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New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00326-16 ◽

2016 ◽

Vol 60 (6) ◽

pp. 3717-3729 ◽

Cited By ~ 24

Author(s):

Jourdan A. Andersson ◽

Eric C. Fitts ◽

Michelle L. Kirtley ◽

Duraisamy Ponnusamy ◽

Alex G. Peniche ◽

...

Keyword(s):

Therapeutic Potential ◽

Bacterial Pathogens ◽

Bactericidal Effect ◽

Resistant Bacteria ◽

Content Type ◽

Broad Applicability ◽

Approved Drugs ◽

Fda Approved Drugs

Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulentYersinia pestisCO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventingY. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy inin vitroscreens, were chosen for further evaluation in a murine model of pneumonic plague to delineate ifin vitroefficacy could be translatedin vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect onY. pestisand having no modulating effect on crucialY. pestisvirulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified fromin vitroscreens, the therapeutic potential of TFP, the most efficacious drugin vivo, was evaluated in murine models ofSalmonella entericaserovar Typhimurium andClostridium difficileinfections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

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The Role of Iron and Siderophores in Infection, and the Development of Siderophore Antibiotics

Clinical Infectious Diseases ◽

10.1093/cid/ciz825 ◽

2019 ◽

Vol 69 (Supplement_7) ◽

pp. S529-S537 ◽

Cited By ~ 21

Author(s):

Malcom G P Page

Keyword(s):

Outer Membrane ◽

Pathogenic Bacteria ◽

Phase 1 ◽

Bacterial Species ◽

Multidrug Resistant ◽

Membrane Receptors ◽

Transport Systems ◽

Resistant Bacteria

Abstract Iron is an essential nutrient for bacterial growth, replication, and metabolism. Humans store iron bound to various proteins such as hemoglobin, haptoglobin, transferrin, ferritin, and lactoferrin, limiting the availability of free iron for pathogenic bacteria. However, bacteria have developed various mechanisms to sequester or scavenge iron from the host environment. Iron can be taken up by means of active transport systems that consist of bacterial small molecule siderophores, outer membrane siderophore receptors, the TonB-ExbBD energy-transducing proteins coupling the outer and the inner membranes, and inner membrane transporters. Some bacteria also express outer membrane receptors for iron-binding proteins of the host and extract iron directly from these for uptake. Ultimately, iron is acquired and transported into the bacterial cytoplasm. The siderophores are small molecules produced and released by nearly all bacterial species and are classified according to the chemical nature of their iron-chelating group (ie, catechol, hydroxamate, α-hydroxyl-carboxylate, or mixed types). Siderophore-conjugated antibiotics that exploit such iron-transport systems are under development for the treatment of infections caused by gram-negative bacteria. Despite demonstrating high in vitro potency against pathogenic multidrug-resistant bacteria, further development of several candidates had stopped due to apparent adaptive resistance during exposure, lack of consistent in vivo efficacy, or emergence of side effects in the host. However, cefiderocol, with an optimized structure, has advanced and has been investigated in phase 1 to 3 clinical trials. This article discusses the mechanisms implicated in iron uptake and the challenges associated with the design and utilization of siderophore-mimicking antibiotics.

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Treatment and Prevention of Staphylococcus epidermidis Experimental Biomaterial-Associated Infection by Bactericidal Peptide 2

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00575-06 ◽

2006 ◽

Vol 50 (12) ◽

pp. 3977-3983 ◽

Cited By ~ 28

Author(s):

Paulus H. S. Kwakman ◽

Anje A. te Velde ◽

Christina M. J. E. Vandenbroucke-Grauls ◽

Sander J. H. van Deventer ◽

Sebastian A. J. Zaat

Keyword(s):

Broad Spectrum ◽

Murine Model ◽

Staphylococcus Epidermidis ◽

Resistant Bacteria ◽

Microbicidal Activity ◽

Treatment And Prevention ◽

Fold Reduction ◽

Cause Of Failure

ABSTRACT Biomaterial-associated infections (BAI) are the major cause of failure of indwelling medical devices and are predominantly caused by staphylococci, especially Staphylococcus epidermidis. We investigated the in vitro microbicidal activity of the synthetic antimicrobial peptide bactericidal peptide 2 (BP2) and its efficacy in a murine model of S. epidermidis BAI. BP2 showed potent microbicidal activity at micromolar concentrations against a broad spectrum of microorganisms, including antibiotic-resistant bacteria. The staphylocidal activity of BP2 was not affected by physiological salt concentrations and was only slightly affected by the presence of human plasma. In the BAI model, injection of BP2 (5 mg/kg of body weight) 1 h after challenge with S. epidermidis resulted in an 80% reduction in the number of culture-positive implants and a 100-fold reduction in survival of S. epidermidis in peri-implant tissue at 24 h postchallenge. When BP2 was injected along implants 3 h prior to bacterial challenge, the median numbers of CFU cultured from biomaterial implants and peri-implant tissue were reduced by 85% and 90%, respectively. In conclusion, BP2 has potent, broad-spectrum in vitro microbicidal activity and showed potent in vivo activity in a murine model of S. epidermidis biomaterial-associated infection.

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Antibiotic Degradation by Commensal Microbes Shields Pathogens

Infection and Immunity ◽

10.1128/iai.00012-20 ◽

2020 ◽

Vol 88 (4) ◽

Author(s):

Mergim Gjonbalaj ◽

James W. Keith ◽

Mytrang H. Do ◽

Tobias M. Hohl ◽

Eric G. Pamer ◽

...

Keyword(s):

Bacterial Species ◽

Pathogen Resistance ◽

Commensal Bacteria ◽

Intestinal Lumen ◽

Resistant Bacteria ◽

Human Populations ◽

Content Type ◽

Antibiotic Degradation

ABSTRACT The complex bacterial populations that constitute the gut microbiota can harbor antibiotic resistance genes (ARGs), including those encoding β-lactamase enzymes (BLA), which degrade commonly prescribed antibiotics such as ampicillin. The prevalence of such genes in commensal bacteria has been increased in recent years by the wide use of antibiotics in human populations and in livestock. While transfer of ARGs between bacterial species has well-established dramatic public health implications, these genes can also function in trans within bacterial consortia, where antibiotic-resistant bacteria can provide antibiotic-sensitive neighbors with leaky protection from drugs, as shown both in vitro and in vivo, in models of lung and subcutaneous coinfection. However, whether the expression of ARGs by harmless commensal bacterial species can destroy antibiotics in the intestinal lumen and shield antibiotic-sensitive pathogens is unknown. To address this question, we colonized germfree or wild-type mice with a model intestinal commensal strain of Escherichia coli that produces either functional or defective BLA. Mice were subsequently infected with Listeria monocytogenes or Clostridioides difficile, followed by treatment with oral ampicillin. The production of functional BLA by commensal E. coli markedly reduced clearance of these pathogens and enhanced systemic dissemination during ampicillin treatment. Pathogen resistance was independent of ARG acquisition via horizontal gene transfer but instead relied on antibiotic degradation in the intestinal lumen by BLA. We conclude that commensal bacteria that have acquired ARGs can mediate shielding of pathogens from the bactericidal effects of antibiotics.

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Phosphatidylinositol-(3,4,5)-Trisphosphate Induces Phagocytosis of NonmotilePseudomonas aeruginosa

Infection and Immunity ◽

10.1128/iai.00215-18 ◽

2018 ◽

Vol 86 (8) ◽

Cited By ~ 5

Author(s):

Sally Demirdjian ◽

Daniel Hopkins ◽

Hector Sanchez ◽

Michael Libre ◽

Scott A. Gerber ◽

...

Keyword(s):

Pathogenic Bacteria ◽

Bacterial Pathogen ◽

Human Neutrophils ◽

Resistant Bacteria ◽

Flagellar Motility ◽

Chronic Infections ◽

Gram Negative ◽

Content Type

ABSTRACTPathogenic bacteria that establish chronic infections in immunocompromised patients frequently undergo adaptation or selection for traits that are advantageous for their growth and survival. Clinical isolates ofPseudomonas aeruginosa, a Gram-negative, opportunistic bacterial pathogen, exhibit a temporal transition from a motile to a nonmotile phenotype through loss of flagellar motility during the course of chronic infection. This progressive loss of motility is associated with increased resistance to both antibiotic and immune clearance. We have previously shown that loss of bacterial motility enablesP. aeruginosato evade phagocytic clearance bothin vitroandin vivoand fails to activate the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent phagocytic pathway. Therefore, we tested the hypothesis that clearance of phagocytosis-resistant bacteria could be induced by exogenously pretreating innate immune cells with the Akt-activating molecule phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). Here, we demonstrate that PIP3induces the uptake of nonmotileP. aeruginosaby primary human neutrophils >25-fold, and this effect is phenocopied with the use of murine phagocytes. However, surprisingly, mechanistic studies revealed that the induction of phagocytosis by PIP3occurs because polyphosphoinositides promote bacterial binding by the phagocytes rather than bypassing the requirement for PI3K. Moreover, this induction was selective since the uptake of other nonmotile Gram-negative, but not Gram-positive, bacteria can also be induced by PIP3. Since there is currently no treatment that effectively eradicates chronicP. aeruginosainfections, these findings provide novel insights into a potential methodology by which to induce clearance of nonmotile pathogenic bacteria and into the endogenous determinants of phagocytic recognition ofP. aeruginosa.

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Therapeutic Efficacy of Bacteriophages

10.5772/intechopen.97619 ◽

2021 ◽

Author(s):

Ramasamy Palaniappan ◽

Govindan Dayanithi

Keyword(s):

Antibiotic Therapy ◽

Antibiotic Treatment ◽

Bacterial Infections ◽

Bacterial Species ◽

Resistant Bacteria ◽

Drug Resistant ◽

Bacteriophage Therapy ◽

Drug Resistant Bacteria

Bacteriophages are bacterial cell-borne viruses that act as natural bacteria killers and they have been identified as therapeutic antibacterial agents. Bacteriophage therapy is a bacterial disease medication that is given to humans after a diagnosis of the disease to prevent and manage a number of bacterial infections. The ability of phage to invade and destroy their target bacterial host cells determines the efficacy of bacteriophage therapy. Bacteriophage therapy, which can be specific or nonspecific and can include a single phage or a cocktail of phages, is a safe treatment choice for antibiotic-resistant and recurrent bacterial infections after antibiotics have failed. A therapy is a cure for health problems, which is administered after the diagnosis of the diseases in the patient. Such non-antibiotic treatment approaches for drug-resistant bacteria are thought to be a promising new alternative to antibiotic therapy and vaccination. The occurrence, biology, morphology, infectivity, lysogenic and lytic behaviours, efficacy, and mechanisms of bacteriophages’ therapeutic potentials for control and treatment of multidrug-resistant/sensitive bacterial infections are discussed. Isolation, long-term storage and recovery of lytic bacteriophages, bioassays, in vivo and in vitro experiments, and bacteriophage therapy validation are all identified. Holins, endolysins, ectolysins, and bacteriocins are bacteriophage antibacterial enzymes that are specific. Endolysins cause the target bacterium to lyse instantly, and hence their therapeutic potential has been explored in “Endolysin therapy.” Endolysins have a high degree of biochemical variability, with certain lysins having a wider bactericidal function than antibiotics, while their bactericidal activities are far narrower. Bacteriophage recombinant lysins (chimeric streptococcal–staphylococcal constructs) have high specificity for a single bacterial species, killing only that species (lysin (CF-301) is focused to kill methicillin resistant Staphylococcus aureus (MRSA)), while other lysins have a broader lytic activity, killing several different bacterial species and hence the range of bactericidal activity. New advances in medicine, food safety, agriculture, and biotechnology demonstrate molecular engineering, such as the optimization of endolysins for particular applications. Small molecule antibiotics are replaced by lysins. The chapter discusses the occurrences of lytic phage in pathogenic bacteria in animals and humans, as well as the possible therapeutic effects of endolysins-bacteriophage therapy in vivo and in vitro, demonstrating the utility and efficacy of the therapy. Further developments in the bacteriophage assay, unique molecular-phage therapy, or a cocktail of phage for the control of a broad range of drug-resistant bacteria-host systems can promote non-antibiotic treatment methods as a viable alternative to conventional antibiotic therapy.

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Arene-Ruthenium(II) Complexes with Carbothiamidopyrazoles as a Potential Alternative for Antibiotic Resistance in Human

Molecules ◽

10.3390/molecules27020468 ◽

2022 ◽

Vol 27 (2) ◽

pp. 468

Author(s):

Ewelina Namiecińska ◽

Magdalena Grazul ◽

Beata Sadowska ◽

Marzena Więckowska-Szakiel ◽

Paweł Hikisz ◽

...

Keyword(s):

Staphylococcus Epidermidis ◽

Synergistic Effects ◽

Bactericidal Effect ◽

Dpph Assay ◽

Human Foreskin Fibroblasts ◽

Potential Alternative ◽

Normal Human ◽

Microbial Dna

To meet the demand for alternatives to commonly used antibiotics, this paper evaluates the antimicrobial potential of arene-ruthenium(II) complexes and their salts, which may be of value in antibacterial treatment. Their antimicrobial activity (MIC, MBC/MFC) was examined in vitro against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa, Proteus vulgaris and Candida albicans and compared with classic antibiotics used as therapeutics. Selected arene-ruthenium(II) complexes were found to have synergistic effects with oxacillin and vancomycin against staphylococci. Their bactericidal effect was found to be associated with cell lysis and the ability to cut microbial DNA. To confirm the safety of the tested arene-ruthenium(II) complexes in vivo, their cytotoxicity was also investigated against normal human foreskin fibroblasts (HFF-1). In addition, the antioxidant and thus pro-health potential of the compounds, i.e., their nonenzymatic antioxidant capacity (NEAC), was determined by two different methods: ferric-TPTZ complex and DPPH assay.

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Production of Novel Bioactive Compounds by the Bacteria Associated with Some Marine Sponges of Gulf of Mannar and Palk Bay, Southeast Coast of India

International Journal of Emerging Research in Management and Technology ◽

10.23956/ijermt.v6i8.136 ◽

2018 ◽

Vol 6 (8) ◽

pp. 183

Author(s):

V. Ramadas ◽

G. Chandralega

Keyword(s):

Bioactive Compounds ◽

Bacterial Species ◽

Marine Sponges ◽

Marine Organisms ◽

Gulf Of Mannar ◽

Bacterial Symbionts ◽

Palk Bay ◽

Excellent Source

Sponges, exclusively are aquatic and mostly marine, are found from the deepest oceans to the edge of the sea. There are approximately 15,000 species of sponges in the world, of which, 150 occur in freshwater, but only about 17 are of commercial value. A total of 486 species of sponges have been identified in India. In the Gulf of Mannar and Palk Bay a maximum of 319 species of sponges have been recorded. It has been proved that marine organisms are excellent source of bioactive secondary metabolites and number of compounds of originated from marine organisms had been reported to possess in-vitro and in-vivo immuno stimulatory activity. Extracts from 20 sponge species were tested for bacterial symbionts and bioactive compounds were isolated from such associated bacterial species in the present study.

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Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190318120103 ◽

2019 ◽

Vol 20 (4) ◽

pp. 285-292 ◽

Cited By ~ 5

Author(s):

Abdullah M. Alnuqaydan ◽

Bilal Rah

Keyword(s):

Medicinal Plant ◽

Biological Activities ◽

Wide Spectrum ◽

Biological Properties ◽

In Vivo Model ◽

Drug Candidate ◽

Phytochemical Analysis ◽

Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

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