Interactions of aminoglycoside antibiotics with rRNA

2016 ◽  
Vol 44 (4) ◽  
pp. 987-993 ◽  
Author(s):  
Joanna Trylska ◽  
Marta Kulik
Keyword(s):  
Molecular Dynamics ◽  
Ribosomal Subunit ◽  
Md Simulations ◽  
Aminoglycoside Antibiotics ◽  
Computational Studies ◽  
Gram Negative Bacteria ◽  
Protein Synthesis Inhibitors ◽  
Gram Negative ◽  
Adverse Side Effects ◽  
16S Rna

Aminoglycoside antibiotics are protein synthesis inhibitors applied to treat infections caused mainly by aerobic Gram-negative bacteria. Due to their adverse side effects they are last resort antibiotics typically used to combat pathogens resistant to other drugs. Aminoglycosides target ribosomes. We describe the interactions of aminoglycoside antibiotics containing a 2-deoxystreptamine (2-DOS) ring with 16S rRNA. We review the computational studies, with a focus on molecular dynamics (MD) simulations performed on RNA models mimicking the 2-DOS aminoglycoside binding site in the small ribosomal subunit. We also briefly discuss thermodynamics of interactions of these aminoglycosides with their 16S RNA target.

scholarly journals High throughput LSPR and SERS analysis of aminoglycoside antibiotics

The Analyst ◽  
2016 ◽  
Vol 141 (17) ◽  
pp. 5120-5126 ◽  
Author(s):  
Kristy S. McKeating ◽  
Maxime Couture ◽  
Marie-Pier Dinel ◽  
Sylvie Garneau-Tsodikova ◽  
Jean-Francois Masson
Keyword(s):  
Side Effects ◽  
High Throughput ◽  
Aminoglycoside Antibiotics ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Adverse Side Effects

Aminoglycoside antibiotics are used in the treatment of infections caused by Gram-negative bacteria, and are often dispensed only in severe cases due to their adverse side effects.

scholarly journals Activity of RX-04 Pyrrolocytosine Protein Synthesis Inhibitors against Multidrug-Resistant Gram-Negative Bacteria

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Anna Vickers ◽  
Shazad Mushtaq ◽  
Neil Woodford ◽  
Michel Doumith ◽  
David M. Livermore
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Protein Synthesis ◽  
Acinetobacter Baumannii ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Protein Synthesis Inhibitors ◽  
Gram Negative ◽  
Content Type ◽  
Active Analog

ABSTRACT Pyrrolocytosines RX-04A to -D are designed to bind to the bacterial 50S ribosomal subunit differently from currently used antibiotics. The four analogs had broad anti-Gram-negative activity: RX-04A—the most active analog—inhibited 94.7% of clinical Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa at 0.5 to 4 μg/ml, with no MICs of >8 μg/ml. MICs for multidrug-resistant (MDR) carbapenemase producers were up to 2-fold higher than those for control strains; values were highest for one Serratia isolate with porin and efflux lesions. mcr-1 did not affect MICs.

scholarly journals Aerobacterial Vaginosis among Women Attending an Infertility Clinic at a Tertiary Care Hospital in Chennai, India and Susceptibility Pattern of Isolates

2021 ◽  
Author(s):  
Abigail R. Sopia ◽  
Pushpa Innocent D. Joseph ◽  
M. Kalyani ◽  
B. Ananthi ◽  
Suresh Dhanaraj ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Tamil Nadu ◽  
Tertiary Care ◽  
Diffusion Method ◽  
Gram Negative Bacteria ◽  
Care Hospital ◽  
Susceptibility Pattern ◽  
Protein Synthesis Inhibitors ◽  
Gram Positive ◽  
Gram Negative

Genital infections and subsequent vaginosis diagnosed through high vaginal swab in women is caused due to fungi or bacteria. The presented study focused on determining the types, numbers and antibacterial susceptibility pattern of aerobic bacteria causing vaginosis in 147 female patients attending infertility centre in Chennai, Tamil Nadu, India. Candida spp. caused 17% of infections with 15.7% of vaginosis caused by E.coli, Klebsiella spp., Acinetobacter spp., Citrobacter spp. and Gram positive cocci – Methicillin Sensitive Staphylococcus aureus (MSSA), Coagulase Negative Staphylococci(CONS), Staphylococcus aureus and Enterococcus spp. causing 12.9% of vaginitis in the study population. A total of 20 different antibiotics – cell wall inhibitors, protein synthesis inhibitors and nucleic acid synthesis inhibitors; were tested to determine the response of bacterial isolates by Kirby-Bauer disc diffusion method. The study result determined that the most effective drug for treating Gram positive bacterial vaginitis as per CLSI guidelines based on susceptibility pattern as: Linezolid(100%), Gentamycin(91.6%), Amikacin(87.5%),Erythromycin(79.2%), Co-Trimoxazole(72.2%), Ciprofloxacin(65.6%) and least Chloramphenicol(44.3%). High level gentamycin(83.3%) was found to be effective in treating Enterococci. The descending order of susceptibility of Gram negative aerobacteria causing vaginitis as per CLSI guidelines are: Amikacin(87.5%), Gentamycin(82.5%), Cefoperazone sulbactam (76.3%), Ciprofloxacin(68.5%), Ceftazidime(62.5%) and least Amoxyclav(25%).All Gram negative bacteria tested were susceptible to– Imipenem and Meropenem as well as Chloramphenicol. Ceftriaxone (87.5%) and Nitrofurantoin(72.3%) among other antibiotics was effective against Gram negative bacteria while all Enterobacteriaceae members were found to be resistant to tetracycline.

scholarly journals The Hitchhiker’s Guide to the Periplasm: Unexpected Molecular Interactions of Antibiotics Revealed by Considering Crowding Effects in E. coli

2020 ◽  
Author(s):  
Conrado Pedebos ◽  
Iain P. S. Smith ◽  
Alister Boags ◽  
Syma Khalid
Keyword(s):  
Molecular Dynamics ◽  
Antibacterial Agents ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
Crowding Effects ◽  
Therapeutic Mechanism ◽  
Target Membrane ◽  
Dynamics Simulations ◽  
Crowded Environment

AbstractThe periplasm of Gram-negative bacteria is a highly crowded environment comprised of many different molecular species. Antibacterial agents that causes lysis of Gram-negative bacteria by their action against the inner membrane must cross the periplasm to arrive at their target membrane. Very little is currently known about their route through the periplasm, and the interactions they experience. To this end, here atomistic molecular dynamics simulations are used to study the path taken by the antibiotic polymyxin B1 through a number of models of the periplasm which are crowded with proteins and osmolytes to different extents. The simulations reveal that PMB1 forms transient and long-lived interactions with proteins and osmolytes that are free in solution as well as lipoproteins anchored to the outer membrane and bound to the cell wall. We show that PMB1 may be able to ‘hitchhike’ within the periplasm by binding to lipoprotein carriers. Overall our results show that PMB1 is rarely uncomplexed within the periplasm; an important consideration for interpretations of its therapeutic mechanism of action. It is likely that this observation can be extended to other antibiotics that rely on diffusion to cross the periplasm.

scholarly journals Evernimicin Binds Exclusively to the 50S Ribosomal Subunit and Inhibits Translation in Cell-Free Systems Derived from both Gram-Positive and Gram-Negative Bacteria

2000 ◽  
Vol 44 (5) ◽  
pp. 1121-1126 ◽  
Author(s):  
Paul M. McNicholas ◽  
David J. Najarian ◽  
Paul A. Mann ◽  
David Hesk ◽  
Roberta S. Hare ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Dissociation Constants ◽  
Wide Spectrum ◽  
Ribosomal Subunit ◽  
Gram Negative Bacteria ◽  
Metabolic Labeling ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Free Translation

ABSTRACT Evernimicin (SCH 27899) is a new antibiotic with activity against a wide spectrum of gram-positive bacteria and activity against some gram-negative bacteria. Previous metabolic labeling studies indicated that evernimicin specifically inhibited protein synthesis inStaphylococcus aureus. Using a susceptibleEscherichia coli strain, we demonstrated that evernimicin also inhibited protein synthesis in E. coli. In cell-free translation assays with extracts from either E. coli orS. aureus, evernimicin had a 50% inhibitory concentration of approximately 125 nM. In contrast, cell-free systems derived from wheat germ and rabbit reticulocytes were inhibited only by very high levels of evernimicin. Evernimicin did not promote transcript misreading. [14C]evernimicin specifically bound to the 50S subunit from E. coli. Nonlinear regression analysis of binding data generated with 70S ribosomes from E. coli andS. aureus and 50S subunits from E. colireturned dissociation constants of 84, 86, and 160 nM, respectively. In binding experiments, performed in the presence of excess quantities of a selection of antibiotics known to bind to the 50S subunit, only the structurally similar drug avilamycin blocked binding of [14C]evernimicin to ribosomes.

scholarly journals Development of Thiazolidinones as Fungal Carbonic Anhydrase Inhibitors

2020 ◽  
Vol 21 (8) ◽  
pp. 2960
Author(s):  
Özlen Güzel-Akdemir ◽  
Simone Carradori ◽  
Rossella Grande ◽  
Kübra Demir-Yazıcı ◽  
Andrea Angeli ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Antibacterial Activity ◽  
Molecular Docking ◽  
Carbonic Anhydrase ◽  
Candida Glabrata ◽  
Gram Negative Bacteria ◽  
Candida Spp ◽  
Gram Negative ◽  
Antifungal Effects ◽  
Putative Mechanism

In our efforts to find new and selective thiazolidinone-based anti-Candida agents, we synthesized and tested 26 thiazolidinones against several Candida spp. and Gram-positive and Gram-negative bacteria. The compounds showed selective antifungal activity with potency similar to fluconazole and clotrimazole, while lacking strong antibacterial activity. Molecular docking and molecular dynamics studies were performed on Candida CYP51a1 and carbonic anhydrase (CA) enzymes to further suggest putative targets that could mediate the antifungal effects of these compounds. Finally, the compounds were tested in enzyme inhibition assays to assess their putative mechanism of action and showed promising KI values in the 0.1–10 µM range against the Candida glabrata β-CA enzyme CgNce103.

The membranes of Gram-negative bacteria: progress in molecular modelling and simulation

2015 ◽  
Vol 43 (2) ◽  
pp. 162-167 ◽  
Author(s):  
Syma Khalid ◽  
Nils A. Berglund ◽  
Daniel A. Holdbrook ◽  
Yuk M. Leung ◽  
Jamie Parkin
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid Bilayers ◽  
Molecular Modelling ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bacterial Membranes ◽  
Lipid Species ◽  
Membrane Models ◽  
Dynamics Simulations

Molecular modelling and simulations have been employed to study the membranes of Gram-negative bacteria for over 20 years. Proteins native to these membranes, as well as antimicrobial peptides and drug molecules have been studied using molecular dynamics simulations in simple models of membranes, usually only comprising one lipid species. Thus, traditionally, the simulations have reflected the majority of in vitro membrane experimental setups, enabling observations from the latter to be rationalized at the molecular level. In the last few years, the sophistication and complexity of membrane models have improved considerably, such that the heterogeneity of the lipid and protein composition of the membranes can now be considered both at the atomistic and coarse-grain levels of granularity. Importantly this means relevant biology is now being retained in the models, thereby linking the in silico and in vivo scenarios. We discuss recent progress in simulations of proteins in simple lipid bilayers, more complex membrane models and finally describe some efforts to overcome timescale limitations of atomistic molecular dynamics simulations of bacterial membranes.

scholarly journals Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Runrun Wu ◽  
Jeremy W. Bakelar ◽  
Karl Lundquist ◽  
Zijian Zhang ◽  
Katie M. Kuo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Single Unit ◽  
Outer Membrane Proteins ◽  
Conformational Dynamics ◽  
Accessory Proteins ◽  
Gram Negative Bacteria ◽  
Folding Intermediate ◽  
Gram Negative ◽  
Dynamics Simulations

AbstractIn Gram-negative bacteria, the biogenesis of β-barrel outer membrane proteins is mediated by the β-barrel assembly machinery (BAM). The mechanism employed by BAM is complex and so far- incompletely understood. Here, we report the structures of BAM in nanodiscs, prepared using polar lipids and native membranes, where we observe an outward-open state. Mutations in the barrel domain of BamA reveal that plasticity in BAM is essential, particularly along the lateral seam of the barrel domain, which is further supported by molecular dynamics simulations that show conformational dynamics in BAM are modulated by the accessory proteins. We also report the structure of BAM in complex with EspP, which reveals an early folding intermediate where EspP threads from the underside of BAM and incorporates into the barrel domain of BamA, supporting a hybrid-barrel budding mechanism in which the substrate is folded into the membrane sequentially rather than as a single unit.

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