scholarly journals Unique Mode of Cell Division by the Mycobacterial Genetic Resister Clones Emerging De Novo from the Antibiotic-Surviving Population

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Kishor Jakkala ◽  
Avraneel Paul ◽  
Atul Pradhan ◽  
Rashmi Ravindran Nair ◽  
Deepti Sharan ◽  
...  
Keyword(s):  
Cell Division ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
De Novo ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Cellular Processes ◽  
Unique Mode

ABSTRACT The emergence of antibiotic genetic resisters of pathogenic bacteria poses a major public health challenge. The mechanism by which bacterial antibiotic genetic resister clones formed de novo multiply and establish a resister population remained unknown. Here, we delineated the unique mode of cell division of the antibiotic genetic resisters of Mycobacterium smegmatis and Mycobacterium tuberculosis formed de novo from the population surviving in the presence of bactericidal concentrations of rifampicin or moxifloxacin. The cells in the rifampicin/moxifloxacin-surviving population generated elevated levels of hydroxyl radical-inflicting mutations. The genetic mutants selected against rifampicin/moxifloxacin became multinucleated and multiseptated and developed multiple constrictions. These cells stochastically divided multiple times, producing sister-daughter cells phenomenally higher in number than what could be expected from their generation time. This caused an abrupt, unexpectedly high increase in the rifampicin/moxifloxacin resister colonies. This unique cell division behavior was not shown by the rifampicin resisters formed naturally in the actively growing cultures. We could detect such abrupt increases in the antibiotic resisters in others’ and our earlier data on the antibiotic-exposed laboratory/clinical M. tuberculosis strains, M. smegmatis and other bacteria in in vitro cultures, infected macrophages/animals, and tuberculosis patients. However, it went unnoticed/unreported in all those studies. This phenomenon occurring in diverse bacteria surviving against different antibiotics revealed the broad significance of the present study. We speculate that the antibiotic-resistant bacillary clones, which emerge in patients with diverse bacterial infections, might be using the same mechanism to establish an antibiotic resister population quickly in the continued presence of antibiotics. IMPORTANCE The bacterial pathogens that are tolerant to antibiotics and survive in the continued presence of antibiotics have the chance to acquire genetically resistant mutations against the antibiotics and emerge de novo as antibiotic resisters. Once the antibiotic resister clone has emerged, often with compromise on growth characteristics, for the protection of the species, it is important to establish an antibiotic-resistant population quickly in the continued presence of the antibiotic. In this regard, the present study has unraveled multinucleation and multiseptation followed by multiple constrictions as the cellular processes used by the bacteria for quick multiplication to establish antibiotic-resistant populations. The study also points out the same phenomenon occurring in other bacterial systems investigated in our laboratory and others’ laboratories. Identification of these specific cellular events involved in quick multiplication offers additional cellular processes that can be targeted in combination with the existing antibiotics’ targets to preempt the emergence of antibiotic-resistant bacterial strains.

scholarly journals TSPphg Lysin from the Extremophilic Thermus Bacteriophage TSP4 as a Potential Antimicrobial Agent against Both Gram-Negative and Gram-Positive Pathogenic Bacteria

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 192 ◽  
Author(s):  
Feng Wang ◽  
Xinyu Ji ◽  
Qiupeng Li ◽  
Guanling Zhang ◽  
Jiani Peng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Infection Model ◽  
Bacterial Cells ◽  
Skin Damage ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Negative

New strategies against antibiotic-resistant bacterial pathogens are urgently needed but are not within reach. Here, we present in vitro and in vivo antimicrobial activity of TSPphg, a novel phage lysin identified from extremophilic Thermus phage TSP4 by sequencing its whole genome. By breaking down the bacterial cells, TSPphg is able to cause bacteria destruction and has shown bactericidal activity against both Gram-negative and Gram-positive pathogenic bacteria, especially antibiotic-resistant strains of Klebsiella pneumoniae, in which the complete elimination and highest reduction in bacterial counts by greater than 6 logs were observed upon 50 μg/mL TSPphg treatment at 37 °C for 1 h. A murine skin infection model further confirmed the in vivo efficacy of TSPphg in removing a highly dangerous and multidrug-resistant Staphylococcus aureus from skin damage and in accelerating wound closure. Together, our findings may offer a therapeutic alternative to help fight bacterial infections in the current age of mounting antibiotic resistance, and to shed light on bacteriophage-based strategies to develop novel anti-infectives.

scholarly journals UVC Light Prophylaxis for Cutaneous Wound Infections in Mice

2012 ◽  
Vol 56 (7) ◽  
pp. 3841-3848 ◽  
Author(s):  
Tianhong Dai ◽  
Barbara Garcia ◽  
Clinton K. Murray ◽  
Mark S. Vrahas ◽  
Michael R. Hamblin
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Light Exposure ◽  
Dna Lesions ◽  
Bacterial Cells ◽  
Wound Infections ◽  
Content Type ◽  
Cutaneous Wound ◽  
Thickness Skin

ABSTRACTUVC light has long been known to be highly germicidal but has not been much developed as a therapy for infections. This study investigated the potential of UVC light for the prophylaxis of infections developing in highly contaminated superficial cutaneous wounds.In vitrostudies demonstrated that the pathogenic bacteriaPseudomonas aeruginosaandStaphylococcus aureuswere inactivated at UVC light exposures much lower than those needed for a similar effect on mammalian keratinocytes. Mouse models of partial-thickness skin abrasions infected with bioluminescentP. aeruginosaandS. aureuswere developed. Approximately 107bacterial cells were inoculated onto wounds measuring 1.2 by1.2 cm on the dorsal surfaces of mice. UVC light was delivered at 30 min after bacterial inoculation. It was found that for both bacterial infections, UVC light at a single radiant exposure of 2.59 J/cm2reduced the bacterial burden in the infected mouse wounds by approximately 10-fold in comparison to those in untreated mouse wounds (P< 0.00001). Furthermore, UVC light increased the survival rate of mice infected withP. aeruginosaby 58.3% (P= 0.0023) and increased the wound healing rate in mice infected withS. aureusby 31.2% (P< 0.00001). DNA lesions were observed in the UVC light-treated mouse wounds; however, the lesions were extensively repaired by 48 h after UVC light exposure. These results suggested that UVC light may be used for the prophylaxis of cutaneous wound infections.

In-vitro evaluation of cisplatin nanoparticles encompass natural polymer

2020 ◽  
Vol 3 (1) ◽  
pp. 1-6
Author(s):  
Bhavani J ◽  
Sunil Kumar Prajapati ◽  
Ravichandran S
Keyword(s):  
Antibacterial Activity ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Bacterial Species ◽  
Research Work ◽  
Dilution Method ◽  
Bacterial Strains ◽  
Active Components ◽  
Synthetic Drugs

Opportunistic bacterial infections are common in the various parts of human body. In recent years bacterial species have shown resistance against a number of synthetic drugs. This study measured the antibacterial activity of bacterial strains against five common pathogenic bacteria related strains. Cup plate method and two fold serial dilution method were used to evaluated by antibacterial activity by the help of different bacterial related strains. The results revealed that Cisplatin (CIP) using natural as a polymer showed a minimum inhibitory concentration (MIC) at 250 mg/ml to 500 mg/ml of the broth against all bacterial strains. CIP using natural as a polymer was prepared different doses1000 μg/ml and 2000 μg/ ml and measured zone of inhibition dose dementedly reduced when compared to standard. The CIP using natural as a polymer exhibited strong anti-bacterial activity against five different species of bacteria and this may be attributed to various active components. Our research work has been indicated Nanoparticles containing CIP using natural as a polymer formulated for the enhanced anti-cancer activity through antimicrobial mechanism. 

scholarly journals Identification of Quorum-Sensing Inhibitors Disrupting Signaling between Rgg and Short Hydrophobic Peptides in Streptococci

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Chaitanya Aggarwal ◽  
Juan Cristobal Jimenez ◽  
Hyun Lee ◽  
George E. Chlipala ◽  
Kiira Ratia ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Communication Networks ◽  
Drug Targets ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Chemical Compounds ◽  
Content Type ◽  
Hydrophobic Peptides ◽  
Biofilm Development

ABSTRACTBacteria coordinate a variety of social behaviors, important for both environmental and pathogenic bacteria, through a process of intercellular chemical signaling known as quorum sensing (QS). As microbial resistance to antibiotics grows more common, a critical need has emerged to develop novel anti-infective therapies, such as an ability to attenuate bacterial pathogens by means of QS interference. Rgg quorum-sensing pathways, widespread in the phylumFirmicutes, employ cytoplasmic pheromone receptors (Rgg transcription factors) that directly bind and elicit gene expression responses to imported peptide signals. In the human-restricted pathogenStreptococcus pyogenes, the Rgg2/Rgg3 regulatory circuit controls biofilm development in response to the short hydrophobic peptides SHP2 and SHP3. Using Rgg-SHP as a model receptor-ligand target, we sought to identify chemical compounds that could specifically inhibit Rgg quorum-sensing circuits. Individual compounds from a diverse library of known drugs and drug-like molecules were screened for their ability to disrupt complexes of Rgg and FITC (fluorescein isothiocyanate)-conjugated SHP using a fluorescence polarization (FP) assay. The best hits were found to bind Rgg3in vitrowith submicromolar affinities, to specifically abolish transcription of Rgg2/3-controlled genes, and to prevent biofilm development inS. pyogeneswithout affecting bacterial growth. Furthermore, the top hit, cyclosporine A, as well as its nonimmunosuppressive analog, valspodar, inhibited Rgg-SHP pathways in multiple species ofStreptococcus. The Rgg-FITC-peptide-based screen provides a platform to identify inhibitors specific for each Rgg type. Discovery of Rgg inhibitors constitutes a step toward the goal of manipulating bacterial behavior for purposes of improving health.IMPORTANCEThe global emergence of antibiotic-resistant bacterial infections necessitates discovery not only of new antimicrobials but also of novel drug targets. Since antibiotics restrict microbial growth, strong selective pressures to develop resistance emerge quickly in bacteria. A new strategy to fight microbial infections has been proposed, namely, development of therapies that decrease pathogenicity of invading organisms while not directly inhibiting their growth, thus decreasing selective pressure to establish resistance. One possible means to this goal is to interfere with chemical communication networks used by bacteria to coordinate group behaviors, which can include the synchronized expression of genes that lead to disease. In this study, we identified chemical compounds that disrupt communication pathways regulated by Rgg proteins in species ofStreptococcus. Treatment of cultures ofS. pyogeneswith the inhibitors diminished the development of biofilms, demonstrating an ability to control bacterial behavior with chemicals that do not inhibit growth.

scholarly journals Lipopeptide Paenipeptin Analogues Potentiate Clarithromycin and Rifampin against Carbapenem-Resistant Pathogens

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Sun Hee Moon ◽  
En Huang
Keyword(s):  
Bacterial Infections ◽  
Combined Treatment ◽  
Human Kidney ◽  
Antibacterial Efficacy ◽  
Kidney Cell Line ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Low Cytotoxicity

ABSTRACTTwo paenipeptin analogues at 4 μg/ml potentiated clarithromycin and rifampin against carbapenem-resistantAcinetobacter baumanniiandKlebsiella pneumoniaestrains. The combined treatment significantly increased their antibacterial efficacy in a microbiological medium and in human serumin vitroat therapeutically relevant concentrations. Moreover, these two paenipeptin analogues showed low cytotoxicity against a human kidney cell line. Therefore, combination therapy with paenipeptins may be an option for the treatment of antibiotic-resistant bacterial infections.

scholarly journals Conjugative Delivery of CRISPR-Cas9 for the Selective Depletion of Antibiotic-Resistant Enterococci

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Marinelle Rodrigues ◽  
Sara W. McBride ◽  
Karthik Hullahalli ◽  
Kelli L. Palmer ◽  
Breck A. Duerkop
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Conjugative Plasmid ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Resistance Determinants

ABSTRACT The innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) that are recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiont Enterococcus faecalis is associated with HAIs, and some strains are MDR. Therefore, novel strategies to control E. faecalis populations are needed. We previously characterized an E. faecalis type II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here, we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers to E. faecalis for the selective removal of antibiotic resistance genes. Using in vitro competition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistant E. faecalis by several orders of magnitude. Finally, we show that E. faecalis donor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinants in vivo. Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.

scholarly journals Prophage Lysin Ply30 Protects Mice from Streptococcus suis and Streptococcus equi subsp. zooepidemicus Infections

2015 ◽  
Vol 81 (21) ◽  
pp. 7377-7384 ◽  
Author(s):  
Fang Tang ◽  
Dezhi Li ◽  
Haojin Wang ◽  
Zhe Ma ◽  
Chengping Lu ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Streptococcus Suis ◽  
Swine Industry ◽  
Content Type ◽  
Antimicrobial Efficiency ◽  
Streptococcus Equi ◽  
Wide Ph Range

ABSTRACTStreptococcus suisandStreptococcus equisubsp.zooepidemicusare capable of infecting humans and various animals, causing significant problems for the worldwide swine industry. As antibiotic resistance has increased, lysosomal enzymes encoded by phages have shown potential for use against pathogenic bacteria. In this study, a novel bacteriophage lysin, Ply30, encoded by theS. suisprophage phi30c, was recombinantly expressed and purified. Ply30 showed high bacteriolysis activity onS. suisandS. equisubsp.zooepidemicus in vitro. The ratio of the optical density at 600 nm (OD600) with treatment versus the OD600with no treatment for most testedS. suisandS. equisubsp.zooepidemicusstrains decreased from 1 to <0.3 and <0.5, respectively, within 1 h. The results of plate viability assays showed that treated bacteria suffered a 1- to 2-log decrease in CFU within 1 h. The optimal concentration of Ply30 was 50 μg/ml, and the optimal pH was 7. Moreover, Ply30 maintained high activity over a wide pH range (pH 6 to 10). The MICs of Ply30 againstStreptococcusstrains ranged from 16 to 512 μg/ml.In vivo, a 2-mg dose of Ply30 protected 90% (9/10 mice) of mice from infection withS. equisubsp.zooepidemicusand 80% (8/10 mice) of mice from infection withS. suis. Seven days after lysin Ply30 treatment, bacterial loads were significantly decreased in all tested organs and blood compared with those at 1 h postinfection without Ply30 treatment. Ply30 showedin vitroandin vivoantimicrobial efficiency and protected mice against two kinds of bacterial infections, indicating that Ply30 may be an effective therapeutic against streptococci.

scholarly journals Efficiency of combined action of antimicrobial preparations against poly-resistant strains of conditionally-pathogenic bacteria isolated from wounds of surgery patients

2020 ◽  
Vol 11 (3) ◽  
Author(s):  
T. V. Sklyar ◽  
K. V. Lavrentievа ◽  
O. M. Rudas ◽  
О. V. Bilotserkivska ◽  
N. V. Kurahina ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Diffusion Method ◽  
Bacterial Strains ◽  
Disk Diffusion Method ◽  
Antibiotic Resistant ◽  
Simultaneous Application ◽  
Strategic Approach ◽  
Resistant Strains

The strategy of use of combination therapy of antibacterial preparations is being broadly introduced to clinical practice to fight bacterial infections caused by poly-resistant strains of microorganisms. From the wounds of surgery patients, we isolated 67 clinical strains of conditionally-pathogenic bacteria identified as Staphylococcus aureus, S. epidermidis, Escherichia coli, Klebsiella pneumoniaе, Proteus vulgaris, Proteus mirabilis, Pseudomonas aeruginosa. Using disk diffusion method, the isolated bacterial strains were found to be most resistant to penicillin preparations: ampicillin, oxacillin, amoxicillin/clavulanat; tetracycline and cephalosporin of the II generation – cefoxitin. The percentage of strains insusceptible to these antibacterial preparations accounted for 65.0%. The division of antibiotic-resistant cultures regarding phenotype groups according to the level of their antibiotic resistance allowed determination of 4 PDR-, 8 XDR- and 14 MDR-strains. During the studies on experimental determining of MIC of antibiotic and antiseptics in the condition of applying them as monopreparations against isolated bacterial cultures, we saw significant exceess in the threshold values of MIC, and, first of all, regarding pandrug-resistant and extensive drug-resistant clinical microbial isolates. Use of combinations of antibacterial preparations was found to show the synergic effect of antibiotics (ceftriaxone, ofloxacin, gentamicin) and antiseptics (chlorhexidine, decasan), which is expressed in simultaneous decrease in MIC of each of the tested preparations by 2–8 times compared with their isolative application. Such combinatory approach regarding simultaneous application of antibacterial preparations may be considered as one of the most promising ways to combat poly-resistant clinical isolates of conditionally-pathogenic microorganisms and to offer a new strategic approach to prevention of spread of antibiotic resistance as a phenomenon in medical practice.

scholarly journals An Organoselenium Compound Inhibits Staphylococcus aureus Biofilms on Hemodialysis CathetersIn Vivo

2011 ◽  
Vol 56 (2) ◽  
pp. 972-978 ◽  
Author(s):  
Phat L. Tran ◽  
Nathan Lowry ◽  
Thomas Campbell ◽  
Ted W. Reid ◽  
Daniel R. Webster ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pathogenic Bacteria ◽  
Antimicrobial Agents ◽  
Bloodstream Infections ◽  
Organoselenium Compound ◽  
Central Venous ◽  
Antibiotic Resistant ◽  
Content Type

ABSTRACTColonization of central venous catheters (CVCs) by pathogenic bacteria leads to catheter-related bloodstream infections (CRBSIs). These colonizing bacteria form highly antibiotic-resistant biofilms.Staphylococcus aureusis one of the most frequently isolated pathogens in CRBSIs. Impregnating CVC surfaces with antimicrobial agents has various degrees of effectiveness in reducing the incidence of CRBSIs. We recently showed that organoselenium covalently attached to disks as an antibiofilm agent inhibited the development ofS. aureusbiofilms. In this study, we investigated the ability of an organoselenium coating on hemodialysis catheters (HDCs) to inhibitS. aureusbiofilmsin vitroandin vivo.S. aureusfailed to develop biofilms on HDCs coated with selenocyanatodiacetic acid (SCAA) in either static or flowthrough continuous-culture systems. The SCAA coating also inhibited the development ofS. aureusbiofilms on HDCsin vivofor 3 days. The SCAA coating was stable and nontoxic to cell culture or animals. This new method for coating the internal and external surfaces of HDCs with SCAA has the potential to prevent catheter-related infections due toS. aureus.

scholarly journals Ajoene, a Sulfur-Rich Molecule from Garlic, Inhibits Genes Controlled by Quorum Sensing

2012 ◽  
Vol 56 (5) ◽  
pp. 2314-2325 ◽  
Author(s):  
Tim Holm Jakobsen ◽  
Maria van Gennip ◽  
Richard Kerry Phipps ◽  
Meenakshi Sundaram Shanmugham ◽  
Louise Dahl Christensen ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Treatment Strategies ◽  
Significant Inhibition ◽  
Control Group ◽  
Content Type ◽  
Multiresistant Bacteria

ABSTRACTIn relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high-priority research area. Quorum sensing (QS), a communication system used by pathogenic bacteria likePseudomonas aeruginosato synchronize the expression of specific genes involved in pathogenicity, is a possible drug target. Previousin vitroandin vivostudies revealed a significant inhibition ofP. aeruginosaQS by crude garlic extract. By bioassay-guided fractionation of garlic extracts, we determined the primary QS inhibitor present in garlic to be ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensivein vitroandin vivostudies, the effect of synthetic ajoene towardP. aeruginosawas elucidated. DNA microarray studies of ajoene-treatedP. aeruginosacultures revealed a concentration-dependent attenuation of a few but central QS-controlled virulence factors, including rhamnolipid. Furthermore, ajoene treatment ofin vitrobiofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a mouse model of pulmonary infection, a significant clearing of infectingP. aeruginosawas detected in ajoene-treated mice compared to a nontreated control group. This study adds to the list of examples demonstrating the potential of QS-interfering compounds in the treatment of bacterial infections.

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