scholarly journals Mutasynthetic Production and Antimicrobial Characterization of Darobactin Analogs

2021 ◽  
Vol 9 (3) ◽  
Author(s):  
Nils Böhringer ◽  
Robert Green ◽  
Yang Liu ◽  
Ute Mettal ◽  
Michael Marner ◽  
...  

Therapeutic options to combat Gram-negative bacterial pathogens are dwindling with increasing antibiotic resistance. This study presents a proof of concept for the heterologous-expression approach to expand on the novel antibiotic class of darobactins and to generate analogs with different activities and pharmacokinetic properties.

2020 ◽  
Vol 22 (12) ◽  
pp. 5125-5136 ◽  
Author(s):  
Zhibo Li ◽  
Parichita Chakraborty ◽  
Reinder H. Vries ◽  
Chunxu Song ◽  
Xinghong Zhao ◽  
...  

mBio ◽  
2021 ◽  
Author(s):  
Jaime E. Zlamal ◽  
Semen A. Leyn ◽  
Mallika Iyer ◽  
Marinela L. Elane ◽  
Nicholas A. Wong ◽  
...  

The challenge of spreading antibiotic resistance calls for systematic efforts to develop more “irresistible” drugs based on a deeper understanding of dynamics and mechanisms of antibiotic resistance acquisition. To address this challenge, we have established a comparative resistomics approach which combines experimental evolution in a continuous-culturing device, the morbidostat, with ultradeep sequencing of evolving microbial populations to identify evolutionary trajectories (mutations and genome rearrangements) leading to antibiotic resistance over a range of target pathogens.


2019 ◽  
Author(s):  
Segen Tekle Gebre-egziabher ◽  
Feleke Moges Yehuala ◽  
Zemene Tigabu Kebede ◽  
Alem Getaneh Mehari

Abstract Abstract Background: The burden of bloodstream infection and antibiotic resistance in intensive care unit (ICU) is high when compared with other settings. The data on the changing antibiotic resistance trends are important for infection control activities. There is no sufficient data in the intensive care units of this hospital. Objective: The aims of this study were to assess the magnitude and risk factors of bacterial pathogens and their antibiotic resistance patterns of blood culture isolates from ICU patients at the University of Gondar Comprehensive Specialized Hospital, Gondar, Ethiopia. Materials and Methods: A cross-sectional study was conducted from February to May 2018.Blood specimen were collected from 384 patients and inoculated on appropriate culture media. Identification of bacterial pathogens and antibiotic susceptibility tests were performed using bacteriological standard methods. Presence of Extended Spectrum Beta Lactamase (ESBL) enzymes was confirmed by combined disk diffusion method. Data were analyzed using SPSS version 20. Result: Of the total 384 study participants, 96(25%) were culture positive. Majority of bacteria isolates 67(69.8%) were Gram negative. The commonly isolated bacterial species were K.pneumoniae 18(18.8%), Coagulase negative Staphylococcus 13(13.5%), K.ozanae 10(10.4%), K.rhinose 8(8.3%) and E.coli, E.cloacae, Citrobacter species, S.aureus each accounts 7(7.3%). Gram negative isolates were found to be resistant to ampicillin 66(98%), amoxicillin/clavulanate 64(95%) and ceftriaxone 52(77.6%). However, amikacin 64(95.5%), meropenem 58(87%) and Ciprofloxacin 56(83.6%) were relatively effective drugs. Gram positive isolates were found to be resistant to Penicillin 28(96.5%), amoxicillin/clavulanate27 (93.1%) and erythromycin 26(90%). They were sensitive to ciprofloxacin 22(79%) and clindamycin 24(83%). Methicillin resistant S.aureus accounted 4(57.1%) and ESBL enzyme producing Gram negative isolates accounted 41(78.8%). Conclusion: Klebsiella species were the predominant bacterial isolates in ICU settings. Antibiotic resistance due to ESBL enzyme production is alarmingly high. This result might be a reflection of inappropriate use of antibiotics and poor infection prevention control practice in these settings. Key words: Antibiotic resistance, ICU, ESBL, Gondar Ethiopia.


2013 ◽  
Vol 3 (1) ◽  
pp. 19-23
Author(s):  
T. O. Femi‐Ola ◽  
T. O. Oladokun ◽  
S. O. Osidero

The antibiotic resistance pattern of bacteria associated with the gut of Centrocestus formosanus, an aggressive wood‐eating termite was investigated. The bacterial isolates encountered were Serratia marcescens, Acetobacter posterianus, Flavobacterium rigense, Xanthomonas spp, Citrobacter freundii, Erwinia cacticida, Aeromonas salmonicida, Enterobacter cloacae, Bacillus mengaterium, Cellulomonas biozota and Lactobacillus fermentii. Among the Gram negative bacterial isolates, resistance to Ceftezidine, and Ampicilin was 100% respectively, while resistance to Ciprofloxacin was 12.5%. However, the Gram positive bacterial isolates showed 100% resistance to Cotrimoxazole, Augmentin, Streptomycin and Chloramphenicol respectively. The least resistance was towards Gentamicin (33.3%). All the bacterial isolates exhibited lipase and protease activity; while 63.6% and 72.7% showed cellulolytic and amylolytic activities respectively.


2018 ◽  
Vol 204 (3) ◽  
pp. 396-405 ◽  
Author(s):  
Amy E. McGrath ◽  
Alexander P. Martyn ◽  
Louise R. Whittell ◽  
Fay E. Dawes ◽  
Jennifer L. Beck ◽  
...  

Marine Drugs ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 128 ◽  
Author(s):  
Jingjing Zhang ◽  
Jiayi Wang ◽  
Tao Feng ◽  
Rui Du ◽  
Xiaorong Tian ◽  
...  

Quorum sensing (QS) is closely associated with the production of multiple virulence factors in bacterial pathogens. N-acyl homoserine lactones (AHLs) are important QS signal molecules that modulate the virulence of gram-negative pathogenic bacteria. Enzymatic degradation of AHLs to interrupt QS, termed quorum quenching (QQ), has been considered a novel strategy for reduction of pathogenicity and prevention of bacterial disease. However, the low expression levels of QQ proteins in the original host bacteria has affected the applications of these proteins. Previously, we identified a novel marine QQ enzyme, named MomL, with high activity and promising biocontrol function. In this study, we linked the target fragment momL to pNCMO2, which provided a basis for the first heterologous expression of MomL in the antifungal and anti-gram-positive-bacteria biocontrol strain Bacillus brevis, and obtaining the recombinant strain named BbMomL. The QQ activity of BbMomL was confirmed using a series of bioassays. BbMomL could not only degrade the exogenous signal molecule C6-HSL, but also the AHL signal molecules produced by the gram-negative pathogens Pectobacterium carotovorum subsp. carotovorum (Pcc) and Pseudomonas aeruginosa PAO1. In addition, BbMomL significantly reduced the secretion of pathogenic factors and the pathogenicity of Pcc and P. aeruginosa PAO1. We tested the biocontrol function of BbMomL for prevention of plant diseases in vitro. The result indicates that BbMomL has a broad antibacterial spectrum. Compared with wild-type B. brevis, BbMomL not only inhibited fungi and gram-positive bacterial pathogens but also considerably inhibited gram-negative bacterial pathogens. Moreover, the Bacillus brevis expression system has good application prospects and is an ideal host for expression and secretion of foreign proteins.


Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 147
Author(s):  
Eliza Depoorter ◽  
Evelien De Canck ◽  
Tom Coenye ◽  
Peter Vandamme

Antimicrobial resistance in Gram-negative pathogens represents a global threat to human health. This study determines the antimicrobial potential of a taxonomically and geographically diverse collection of 263 Burkholderia (sensu lato) isolates and applies natural product dereplication strategies to identify potentially novel molecules. Antimicrobial activity is almost exclusively present in Burkholderia sensu stricto bacteria and rarely observed in the novel genera Paraburkholderia, Caballeronia, Robbsia, Trinickia, and Mycetohabitans. Fourteen isolates show a unique spectrum of antimicrobial activity and inhibited carbapenem-resistant Gram-negative bacterial pathogens. Dereplication of the molecules present in crude spent agar extracts identifies 42 specialized metabolites, 19 of which represented potentially novel molecules. The known identified Burkholderia metabolites include toxoflavin, reumycin, pyrrolnitrin, enacyloxin, bactobolin, cepacidin, ditropolonyl sulfide, and antibiotics BN-227-F and SF 2420B, as well as the siderophores ornibactin, pyochelin, and cepabactin. Following semipreparative fractionation and activity testing, a total of five potentially novel molecules are detected in active fractions. Given the molecular formula and UV spectrum, two of those putative novel molecules are likely related to bactobolins, and another is likely related to enacyloxins. The results from this study confirm and extend the observation that Burkholderia bacteria present exciting opportunities for the discovery of potentially novel bioactive molecules.


mBio ◽  
2014 ◽  
Vol 5 (5) ◽  
Author(s):  
Andrew P. Tomaras ◽  
Craig J. McPherson ◽  
Michael Kuhn ◽  
Arlene Carifa ◽  
Lisa Mullins ◽  
...  

ABSTRACT The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discovery of small-molecule inhibitors of LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A, represents a clinically unprecedented strategy to specifically act against Gram-negative organisms such as Pseudomonas aeruginosa and members of the Enterobacteriaceae. In this report, we describe the microbiological characterization of LpxC-4, a recently disclosed inhibitor of this bacterial target, and demonstrate that its spectrum of activity extends to several of the pathogenic species that are most threatening to human health today. We also show that spontaneous generation of LpxC-4 resistance occurs at frequencies comparable to those seen with marketed antibiotics, and we provide an in-depth analysis of the mechanisms of resistance utilized by target pathogens. Interestingly, these isolates also served as tools to further our understanding of the regulation of lipid A biosynthesis and enabled the discovery that this process occurs very distinctly between P. aeruginosa and members of the Enterobacteriaceae. Finally, we demonstrate that LpxC-4 is efficacious in vivo against multiple strains in different models of bacterial infection and that the major first-step resistance mechanisms employed by the intended target organisms can still be effectively treated with this new inhibitor. IMPORTANCE New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community. The limited number of validated cellular targets and approaches, along with the increasing amount of antibiotic resistance that is spreading throughout the clinical environment, has prompted us to explore the utility of inhibitors of novel targets and pathways in these resistant organisms, since preexisting target-based resistance should be negligible. Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane. In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic.


2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Walelign Dessie ◽  
Gebru Mulugeta ◽  
Surafael Fentaw ◽  
Amete Mihret ◽  
Mulu Hassen ◽  
...  

Background. The emergence of multidrug resistant bacterial pathogens in hospitals is becoming a challenge for surgeons to treat hospital acquired infections.Objective. To determine bacterial pathogens and drug susceptibility isolated from surgical site infections at St. Paul Specialized Hospital Millennium Medical College and Yekatit 12 Referral Hospital Medical College, Addis Ababa, Ethiopia.Methods. A cross-sectional study was conducted between October 2013 and March 2014 on 107 surgical site infected patients. Wound specimens were collected using sterile cotton swab and processed as per standard operative procedures in appropriate culture media; and susceptibility testing was done using Kirby-Bauer disc diffusion technique. The data were analyzed by using SPSS version 20.Result. From a total of 107 swabs collected, 90 (84.1%) were culture positive and 104 organisms were isolated.E. coli(24 (23.1%)) was the most common organism isolated followed by multidrug resistantAcinetobacterspecies (23 (22.1%)). More than 58 (75%) of the Gram negative isolates showed multiple antibiotic resistance (resistance ≥ 5 drugs). Pan-antibiotic resistance was noted among 8 (34.8%)Acinetobacterspecies and 3 (12.5%)E. coli. This calls for abstinence from antibiotic abuse.Conclusion. Gram negative bacteria were the most important isolates accounting for 76 (73.1%). Ampicillin, amoxicillin, penicillin, cephazoline, and tetracycline showed resistance while gentamicin and ciprofloxacin were relatively effective antimicrobials.


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