Antibiotics

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Open AccessReview

Sub-Optimal Treatment of Bacterial Biofilms

by Tianyan Song, Marylise Duperthuy and Sun Nyunt Wai

Antibiotics 2016, 5(2), 23; https://doi.org/10.3390/antibiotics5020023 - 22 Jun 2016

Cited by 47 | Viewed by 8430

Bacterial biofilm is an emerging clinical problem recognized in the treatment of infectious diseases within the last two decades. The appearance of microbial biofilm in clinical settings is steadily increasing due to several reasons including the increased use of quality of life-improving artificial [...] Read more.

Bacterial biofilm is an emerging clinical problem recognized in the treatment of infectious diseases within the last two decades. The appearance of microbial biofilm in clinical settings is steadily increasing due to several reasons including the increased use of quality of life-improving artificial devices. In contrast to infections caused by planktonic bacteria that respond relatively well to standard antibiotic therapy, biofilm-forming bacteria tend to cause chronic infections whereby infections persist despite seemingly adequate antibiotic therapy. This review briefly describes the responses of biofilm matrix components and biofilm-associated bacteria towards sub-lethal concentrations of antimicrobial agents, which may include the generation of genetic and phenotypic variabilities. Clinical implications of bacterial biofilms in relation to antibiotic treatments are also discussed. Full article

(This article belongs to the Special Issue Biofilm Infection)

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Open AccessReview

Choline Binding Proteins from Streptococcus pneumoniae: A Dual Role as Enzybiotics and Targets for the Design of New Antimicrobials

by Beatriz Maestro and Jesús M. Sanz

Antibiotics 2016, 5(2), 21; https://doi.org/10.3390/antibiotics5020021 - 14 Jun 2016

Cited by 57 | Viewed by 11945

Abstract

Streptococcus pneumoniae (pneumococcus) is an important pathogen responsible for acute invasive and non-invasive infections such as meningitis, sepsis and otitis media, being the major cause of community-acquired pneumonia. The fight against pneumococcus is currently hampered both by insufficient vaccine coverage and by rising [...] Read more.

Streptococcus pneumoniae (pneumococcus) is an important pathogen responsible for acute invasive and non-invasive infections such as meningitis, sepsis and otitis media, being the major cause of community-acquired pneumonia. The fight against pneumococcus is currently hampered both by insufficient vaccine coverage and by rising antimicrobial resistances to traditional antibiotics, making necessary the research on novel targets. Choline binding proteins (CBPs) are a family of polypeptides found in pneumococcus and related species, as well as in some of their associated bacteriophages. They are characterized by a structural organization in two modules: a functional module (FM), and a choline-binding module (CBM) that anchors the protein to the choline residues present in the cell wall through non-covalent interactions. Pneumococcal CBPs include cell wall hydrolases, adhesins and other virulence factors, all playing relevant physiological roles for bacterial viability and virulence. Moreover, many pneumococcal phages also make use of hydrolytic CBPs to fulfill their infectivity cycle. Consequently, CBPs may play a dual role for the development of novel antipneumococcal drugs, both as targets for inhibitors of their binding to the cell wall and as active cell lytic agents (enzybiotics). In this article, we review the current state of knowledge about host- and phage-encoded pneumococcal CBPs, with a special focus on structural issues, together with their perspectives for effective anti-infectious treatments. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Open AccessReview

Chloramphenicol Derivatives as Antibacterial and Anticancer Agents: Historic Problems and Current Solutions

by George P. Dinos, Constantinos M. Athanassopoulos, Dionissia A. Missiri, Panagiota C. Giannopoulou, Ioannis A. Vlachogiannis, Georgios E. Papadopoulos, Dionissios Papaioannou and Dimitrios L. Kalpaxis

Antibiotics 2016, 5(2), 20; https://doi.org/10.3390/antibiotics5020020 - 03 Jun 2016

Cited by 100 | Viewed by 18483

Abstract

Chloramphenicol (CAM) is the D-threo isomer of a small molecule, consisting of a p-nitrobenzene ring connected to a dichloroacetyl tail through a 2-amino-1,3-propanediol moiety. CAM displays a broad-spectrum bacteriostatic activity by specifically inhibiting the bacterial protein synthesis. In certain but important [...] Read more.

Chloramphenicol (CAM) is the D-threo isomer of a small molecule, consisting of a p-nitrobenzene ring connected to a dichloroacetyl tail through a 2-amino-1,3-propanediol moiety. CAM displays a broad-spectrum bacteriostatic activity by specifically inhibiting the bacterial protein synthesis. In certain but important cases, it also exhibits bactericidal activity, namely against the three most common causes of meningitis, Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. Resistance to CAM has been frequently reported and ascribed to a variety of mechanisms. However, the most important concerns that limit its clinical utility relate to side effects such as neurotoxicity and hematologic disorders. In this review, we present previous and current efforts to synthesize CAM derivatives with improved pharmacological properties. In addition, we highlight potentially broader roles of these derivatives in investigating the plasticity of the ribosomal catalytic center, the main target of CAM. Full article

(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)

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Open AccessArticle

Insights into the Stress Response Triggered by Kasugamycin in Escherichia coli

by Christian Müller, Lena Sokol, Oliver Vesper, Martina Sauert and Isabella Moll

Antibiotics 2016, 5(2), 19; https://doi.org/10.3390/antibiotics5020019 - 01 Jun 2016

Cited by 11 | Viewed by 5671

Abstract

The bacteriostatic aminoglycoside antibiotic kasugamycin inhibits protein synthesis at an initial step without affecting translation elongation. It binds to the mRNA track of the ribosome and prevents formation of the translation initiation complex on canonical mRNAs. In contrast, translation of leaderless mRNAs continues [...] Read more.

The bacteriostatic aminoglycoside antibiotic kasugamycin inhibits protein synthesis at an initial step without affecting translation elongation. It binds to the mRNA track of the ribosome and prevents formation of the translation initiation complex on canonical mRNAs. In contrast, translation of leaderless mRNAs continues in the presence of the drug in vivo. Previously, we have shown that kasugamycin treatment in E. coli stimulates the formation of protein-depleted ribosomes that are selective for leaderless mRNAs. Here, we provide evidence that prolonged kasugamycin treatment leads to selective synthesis of specific proteins. Our studies indicate that leaderless and short-leadered mRNAs are generated by different molecular mechanisms including alternative transcription and RNA processing. Moreover, we provide evidence for ribosome heterogeneity in response to kasugamycin treatment by alteration of the modification status of the stalk proteins bL7/L12. Full article

(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)

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Open AccessArticle

Ribosome Assembly as Antimicrobial Target

by Rainer Nikolay, Sabine Schmidt, Renate Schlömer, Elke Deuerling and Knud H. Nierhaus

Antibiotics 2016, 5(2), 18; https://doi.org/10.3390/antibiotics5020018 - 27 May 2016

Cited by 15 | Viewed by 9922

Abstract

Many antibiotics target the ribosome and interfere with its translation cycle. Since translation is the source of all cellular proteins including ribosomal proteins, protein synthesis and ribosome assembly are interdependent. As a consequence, the activity of translation inhibitors might indirectly cause defective ribosome [...] Read more.

Many antibiotics target the ribosome and interfere with its translation cycle. Since translation is the source of all cellular proteins including ribosomal proteins, protein synthesis and ribosome assembly are interdependent. As a consequence, the activity of translation inhibitors might indirectly cause defective ribosome assembly. Due to the difficulty in distinguishing between direct and indirect effects, and because assembly is probably a target in its own right, concepts are needed to identify small molecules that directly inhibit ribosome assembly. Here, we summarize the basic facts of ribosome targeting antibiotics. Furthermore, we present an in vivo screening strategy that focuses on ribosome assembly by a direct fluorescence based read-out that aims to identify and characterize small molecules acting as primary assembly inhibitors. Full article

(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)

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Open AccessArticle

The Oligopeptide Permease Opp Mediates Illicit Transport of the Bacterial P-site Decoding Inhibitor GE81112

by Alessandro Maio, Letizia Brandi, Stefano Donadio and Claudio O. Gualerzi

Antibiotics 2016, 5(2), 17; https://doi.org/10.3390/antibiotics5020017 - 24 May 2016

Cited by 22 | Viewed by 6454

Abstract

GE81112 is a tetrapeptide antibiotic that binds to the 30S ribosomal subunit and specifically inhibits P-site decoding of the mRNA initiation codon by the fMet-tRNA anticodon. GE81112 displays excellent microbiological activity against some Gram-positive and Gram-negative bacteria in both minimal and complete, chemically [...] Read more.

GE81112 is a tetrapeptide antibiotic that binds to the 30S ribosomal subunit and specifically inhibits P-site decoding of the mRNA initiation codon by the fMet-tRNA anticodon. GE81112 displays excellent microbiological activity against some Gram-positive and Gram-negative bacteria in both minimal and complete, chemically defined, broth, but is essentially inactive in complete complex media. This is due to the presence of peptides that compete with the antibiotic for the oligopeptide permease system (Opp) responsible for its illicit transport into the bacterial cells as demonstrated in the cases of Escherichia coli and Bacillus subtilis. Mutations that inactivate the Opp system and confer GE81112 resistance arise spontaneously with a frequency of ca. 1 × 10⁻⁶, similar to that of the mutants resistant to tri-l-ornithine, a known Opp substrate. On the contrary, cells expressing extrachromosomal copies of the opp genes are extremely sensitive to GE81112 in rich medium and GE81112-resistant mutations affecting the molecular target of the antibiotic were not detected upon examining >10⁹ cells of this type. However, some mutations introduced in the 16S rRNA to confer kasugamycin resistance were found to reduce the sensitivity of the cells to GE81112. Full article

(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)

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Open AccessArticle

Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1

by Paul P. Ferguson, W. Blake Holloway, William N. Setzer, Hana McFeeters and Robert L. McFeeters

Antibiotics 2016, 5(2), 16; https://doi.org/10.3390/antibiotics5020016 - 10 May 2016

Cited by 5 | Viewed by 6340

Abstract

Peptidyl-tRNA hydrolases (Pths) play ancillary yet essential roles in protein biosynthesis by recycling peptidyl-tRNA. In E. coli, inhibition of bacterial Pth1 leads to accumulation of peptidyl-tRNA, depletion of aminoacyl-tRNA, and cell death. Eukaryotes have multiple Pths and Pth1 knock out was shown [...] Read more.

Peptidyl-tRNA hydrolases (Pths) play ancillary yet essential roles in protein biosynthesis by recycling peptidyl-tRNA. In E. coli, inhibition of bacterial Pth1 leads to accumulation of peptidyl-tRNA, depletion of aminoacyl-tRNA, and cell death. Eukaryotes have multiple Pths and Pth1 knock out was shown to have no effect on viability in yeast. Thereby, bacterial Pth1 is a promising target for novel antibiotic development. With the abundance of Pth1 structural data, molecular docking was used for virtual screening of existing, commercially available antibiotics to map potential interactions with Pth enzymes. Overall, 83 compounds were docked to eight different bacterial Pth1 and three different Pth2 structures. A variety of compounds demonstrated favorable docking with Pths. Whereas, some compounds interacted favorably with all Pths (potential broad spectrum inhibition), more selective interactions were observed for Pth1 or Pth2 and even specificity for individual Pth1s. While the correlation between computational docking and experimentation still remains unknown, these findings support broad spectrum inhibition, but also point to the possibility of narrow spectrum Pth1 inhibition. Also suggested is that Pth1 can be distinguished from Pth2 by small molecule inhibitors. The findings support continued development of Pth1 as an antibiotic target. Full article

(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)

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524 KiB

Open AccessReview

Antibiotics and RNase P

by Denis Drainas

Antibiotics 2016, 5(2), 15; https://doi.org/10.3390/antibiotics5020015 - 06 May 2016

Cited by 5 | Viewed by 5323

Abstract

RNase P is an essential endonuclease in tRNA biogenesis, which generates the mature 5′-termini of tRNAs. Most forms of RNase P are ribonucleoproteins, i.e., they consist of an essential RNA and protein subunits. The catalytic function of ribonucleoprotein RNase P enzymes resides [...] Read more.

RNase P is an essential endonuclease in tRNA biogenesis, which generates the mature 5′-termini of tRNAs. Most forms of RNase P are ribonucleoproteins, i.e., they consist of an essential RNA and protein subunits. The catalytic function of ribonucleoprotein RNase P enzymes resides entirely in the RNA subunit. Its high structural and functional diversity among representatives of a vast variety of phylogenetic domains indicates that RNase P could serve as a molecular target and a useful screening system for the development of new drugs in the battle against bacterial drug resistance. Full article

(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)

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Structural Insights into Protein-Protein Interactions Involved in Bacterial Cell Wall Biogenesis

by Federica Laddomada, Mayara M. Miyachiro and Andréa Dessen

Antibiotics 2016, 5(2), 14; https://doi.org/10.3390/antibiotics5020014 - 28 Apr 2016

Cited by 25 | Viewed by 8925

Abstract

The bacterial cell wall is essential for survival, and proteins that participate in its biosynthesis have been the targets of antibiotic development efforts for decades. The biosynthesis of its main component, the peptidoglycan, involves the coordinated action of proteins that are involved in [...] Read more.

The bacterial cell wall is essential for survival, and proteins that participate in its biosynthesis have been the targets of antibiotic development efforts for decades. The biosynthesis of its main component, the peptidoglycan, involves the coordinated action of proteins that are involved in multi-member complexes which are essential for cell division (the “divisome”) and/or cell wall elongation (the “elongasome”), in the case of rod-shaped cells. Our knowledge regarding these interactions has greatly benefitted from the visualization of different aspects of the bacterial cell wall and its cytoskeleton by cryoelectron microscopy and tomography, as well as genetic and biochemical screens that have complemented information from high resolution crystal structures of protein complexes involved in divisome or elongasome formation. This review summarizes structural and functional aspects of protein complexes involved in the cytoplasmic and membrane-related steps of peptidoglycan biosynthesis, with a particular focus on protein-protein interactions whereby disruption could lead to the development of novel antibacterial strategies. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Antibiotics, Volume 5, Issue 2 (June 2016) – 9 articles

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