scholarly journals Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

2018 ◽  
Vol 14 ◽  
pp. 2881-2896 ◽  
Author(s):  
Laura Carro
Keyword(s):  
Protein Interactions ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Protein Protein Interactions ◽  
Lead Discovery ◽  
Antibiotic Development ◽  
Cellular Processes ◽  
Ppi Networks ◽  
New Antibiotics

Antibiotics are potent pharmacological weapons against bacterial infections; however, the growing antibiotic resistance of microorganisms is compromising the efficacy of the currently available pharmacotherapies. Even though antimicrobial resistance is not a new problem, antibiotic development has failed to match the growth of resistant pathogens and hence, it is highly critical to discover new anti-infective drugs with novel mechanisms of action which will help reducing the burden of multidrug-resistant microorganisms. Protein–protein interactions (PPIs) are involved in a myriad of vital cellular processes and have become an attractive target to treat diseases. Therefore, targeting PPI networks in bacteria may offer a new and unconventional point of intervention to develop novel anti-infective drugs which can combat the ever-increasing rate of multidrug-resistant bacteria. This review describes the progress achieved towards the discovery of molecules that disrupt PPI systems in bacteria for which inhibitors have been identified and whose targets could represent an alternative lead discovery strategy to obtain new anti-infective molecules.

scholarly journals Metabolic profiling and antibacterial activity of Eryngium pristis Cham. & Schltdl. - prospecting for its use in the treatment of bacterial infections

2021 ◽  
Vol 5 (1) ◽  
pp. 020-028
Author(s):  
Fernandes Laura Silva ◽  
da Costa Ygor Ferreira Garcia ◽  
de Bessa Martha Eunice ◽  
Ferreira Adriana Lucia Pires ◽  
do Amaral Corrêa José Otávio ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Bioactive Compounds ◽  
Metabolic Profile ◽  
Bacterial Infections ◽  
Ethanolic Extract ◽  
Multidrug Resistant ◽  
Gas Chromatography Mass Spectrometry ◽  
Resistant Bacteria ◽  
Bacterial Strains ◽  
New Antibiotics

Morbidity and mortality of the infected patients by multidrug-resistant bacteria have increased, emphasizing the urgency of fight for the discovery of new innovative antibiotics. In this sense, natural products emerge as valuable sources of bioactive compounds. Among the biodiversity, Eryngium pristis Cham. & Schltdl. (Apiaceae Lindl.) is traditionally used to treat thrush and ulcers of throat and mouth, as diuretic and emmenagogue, but scarcely known as an antimicrobial agent. With this context in mind, the goals of this study were to investigate the metabolic profile and the antibacterial activity of ethanolic extract (EE-Ep) and hexane (HF-Ep), dichloromethane (DF-Ep), ethyl acetate (EAF-Ep) and butanol (BF-Ep) fractions from E. pristis leaves. Gas Chromatography-Mass Spectrometry (GC-MS) was performed to stablish the metabolic profile and revealed the presence of 12 and 14 compounds in EAF-Ep and HF-Ep, respectively. β-selinene, spathulenol, globulol, 2-methoxy-4-vinylphenol, α-amyrin, β-amyrin, and lupeol derivative were some of phytochemicals identified. The antibacterial activity was determined by Minimal Inhibitory Concentration (MIC) using the broth micro-dilution against eight ATCC® and five methicillin-resistant Staphylococcus aureus (MRSA) clinical strains. HF-Ep was the most effective (MIC ≤ 5,000 µg/µL), being active against the largest part of tested Gram-positive and Gram-negative bacterial strains, including MRSA, with exception of Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 9027) and (ATCC 27853). These results suggest that E. pristis is a natural source of bioactive compounds for the search of new antibiotics which can be an interesting therapeutic approach to recover patients mainly infected by MRSA strains.

scholarly journals Upregulation of gluconeogenesis leads to increased tolerance to antibiotics targeting the MreB elongosome in E. coli

2020 ◽  
Author(s):  
Brody Barton ◽  
Addison Grinnell ◽  
Randy M. Morgenstein
Keyword(s):  
Antibiotic Resistance ◽  
Minimal Inhibitory Concentration ◽  
Bacterial Infections ◽  
Inhibitory Concentration ◽  
Resistance Mechanism ◽  
Tca Cycle ◽  
Resistant Bacteria ◽  
Antibiotic Development ◽  
New Antibiotics ◽  
Global Threat

AbstractAntibiotic resistant bacteria are a global threat to human health. One way to combat the rise of antibiotic resistance is to make new antibiotics that target previously ignored proteins. The bacterial actin homolog, MreB, is highly conserved among rod-shaped bacteria and essential for growth, making MreB a good focus for antibiotic targeting. Therefore, it is imperative to understand mechanisms that can give rise to resistance to MreB targeting drugs. Using the MreB targeting drug, A22, we show that changes to central metabolism through deletion of TCA cycle genes, leads to the upregulation of gluconeogenesis resulting in cells with an increased minimal inhibitory concentration to A22. This phenotype can be recapitulated through the addition of glucose to the media. Finally, we show that this increase in minimal inhibitory concentration is not specific to A22 but can be seen in other cell wall targeting antibiotics, such as mecillinam.ImportanceThe spread of antibiotic resistance has made bacterial infections harder to treat. Finding new targets for antibiotic development is critical to overcoming the variety of resistance mechanism that are already crippling our ability to treat infections with current antibiotics. The bacterial actin homolog MreB is a good target for new antibiotic development because it is essential for growth and highly conserved among rod-shaped pathogens. The significance of this research is in understanding the mechanisms cells can develop toward the inhibition of MreB to better understand how to make MreB targeting antibiotics in the future.

scholarly journals Fosfomycin

2016 ◽  
Vol 29 (2) ◽  
pp. 321-347 ◽  
Author(s):  
Matthew E. Falagas ◽  
Evridiki K. Vouloumanou ◽  
George Samonis ◽  
Konstantinos Z. Vardakas
Keyword(s):  
Bacterial Infections ◽  
Clinical Effectiveness ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Antibiotic Resistant ◽  
Development Of Resistance ◽  
Extensively Drug Resistant ◽  
New Antibiotics

SUMMARYThe treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, thein vitroactivity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

scholarly journals A Synthetic Antibiotic Scaffold Effective Against Multidrug-Resistant Bacterial Pathogens

2021 ◽  
Author(s):  
Matthew Mitcheltree ◽  
Amarnath Pisipati ◽  
Egor A. Syroegin ◽  
Katherine J. Silvestre ◽  
Dorota Klepacki ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Health Concern ◽  
Structural Basis ◽  
Resistant Bacteria ◽  
Global Public Health ◽  
Antibiotic Resistant ◽  
New Antibiotics ◽  
Orally Bioavailable

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern. For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semi-synthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semi-synthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective in strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native 70S bacterial ribosome, as well as the Erm-methylated 70S ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating bacterial infections, testifying to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.

scholarly journals A Synthetic Antibiotic Scaffold Effective Against Multidrug-Resistant Bacterial Pathogens

2021 ◽  
Author(s):  
Matthew Mitcheltree ◽  
Amarnath Pisipati ◽  
Egor A. Syroegin ◽  
Katherine J. Silvestre ◽  
Dorota Klepacki ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Health Concern ◽  
Structural Basis ◽  
Resistant Bacteria ◽  
Global Public Health ◽  
Antibiotic Resistant ◽  
New Antibiotics ◽  
Orally Bioavailable

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern. For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semi-synthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semi-synthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective in strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native 70S bacterial ribosome, as well as the Erm-methylated 70S ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating bacterial infections, testifying to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.

scholarly journals Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Sun Sook Chung ◽  
Joseph C F Ng ◽  
Anna Laddach ◽  
N Shaun B Thomas ◽  
Franca Fraternali
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Interaction Network ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Short Loop ◽  
New Strategy ◽  
Loop Network ◽  
Protein Protein Interaction Network

Abstract Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein–protein interactions (PPIs). Here, we establish an in silico pipeline to identify specific PPI sub-networks containing mutated proteins as potential targets, which we apply to mutation data of four different leukaemias. Our method is based on extracting cyclic interactions of a small number of proteins topologically and functionally linked in the Protein–Protein Interaction Network (PPIN), which we call short loop network motifs (SLM). We uncover a new property of PPINs named ‘short loop commonality’ to measure indirect PPIs occurring via common SLM interactions. This detects ‘modules’ of PPI networks enriched with annotated biological functions of proteins containing mutation hotspots, exemplified by FLT3 and other receptor tyrosine kinase proteins. We further identify functional dependency or mutual exclusivity of short loop commonality pairs in large-scale cellular CRISPR–Cas9 knockout screening data. Our pipeline provides a new strategy for identifying new therapeutic targets for drug discovery.

scholarly journals Antibiotic-Resistant Bacteria in Clams—A Study on Mussels in the River Rhine

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 571
Author(s):  
Nicole Zacharias ◽  
Iris Löckener ◽  
Sarah M. Essert ◽  
Esther Sib ◽  
Gabriele Bierbaum ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Sewage Treatment ◽  
Sewage Treatment Plant ◽  
Treatment Plant ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
River Rhine ◽  
Antibiotic Resistant Bacteria ◽  
Surrounding Water ◽  
Antibiotic Resistant

Bacterial infections have been treated effectively by antibiotics since the discovery of penicillin in 1928. A worldwide increase in the use of antibiotics led to the emergence of antibiotic resistant strains in almost all bacterial pathogens, which complicates the treatment of infectious diseases. Antibiotic-resistant bacteria play an important role in increasing the risk associated with the usage of surface waters (e.g., irrigation, recreation) and the spread of the resistance genes. Many studies show that important pathogenic antibiotic-resistant bacteria can enter the environment by the discharge of sewage treatment plants and combined sewage overflow events. Mussels have successfully been used as bio-indicators of heavy metals, chemicals and parasites; they may also be efficient bio-indicators for viruses and bacteria. In this study an influence of the discharge of a sewage treatment plant could be shown in regard to the presence of E. coli in higher concentrations in the mussels downstream the treatment plant. Antibiotic-resistant bacteria, resistant against one or two classes of antibiotics and relevance for human health could be detected in the mussels at different sampling sites of the river Rhine. No multidrug-resistant bacteria could be isolated from the mussels, although they were found in samples of the surrounding water body.

scholarly journals Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2047
Author(s):  
Magda Ferreira ◽  
Maria Ogren ◽  
Joana N. R. Dias ◽  
Marta Silva ◽  
Solange Gil ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Private Investment ◽  
Therapeutic Index ◽  
Multidrug Resistant ◽  
Current Treatment ◽  
Delivery Systems ◽  
Resistant Bacteria ◽  
Bacterial Cells ◽  
Antimicrobial Drugs

Antimicrobial drugs are key tools to prevent and treat bacterial infections. Despite the early success of antibiotics, the current treatment of bacterial infections faces serious challenges due to the emergence and spread of resistant bacteria. Moreover, the decline of research and private investment in new antibiotics further aggravates this antibiotic crisis era. Overcoming the complexity of antimicrobial resistance must go beyond the search of new classes of antibiotics and include the development of alternative solutions. The evolution of nanomedicine has allowed the design of new drug delivery systems with improved therapeutic index for the incorporated compounds. One of the most promising strategies is their association to lipid-based delivery (nano)systems. A drug’s encapsulation in liposomes has been demonstrated to increase its accumulation at the infection site, minimizing drug toxicity and protecting the antibiotic from peripheral degradation. In addition, liposomes may be designed to fuse with bacterial cells, holding the potential to overcome antimicrobial resistance and biofilm formation and constituting a promising solution for the treatment of potential fatal multidrug-resistant bacterial infections, such as methicillin resistant Staphylococcus aureus. In this review, we aim to address the applicability of antibiotic encapsulated liposomes as an effective therapeutic strategy for bacterial infections.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

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