Designer drugs for discerning bugs

Douthwaite, Stephen

doi:10.1073/pnas.1012547107

Cited by 7 publications

(14 citation statements)

References 20 publications

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“…LM binds in the exit tunnel in a very similar manner to other members of the macrolide antibiotic family, essentially overlapping with the binding site of erythromycin (1,2). Like other members of this family, LM action arises from physically blocking the progression of the nascent peptides through the tunnel.…”

Section: Discussionmentioning

confidence: 97%

Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit

Belousoff

Shapira

Bashan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The structures of the large ribosomal subunit of Deinococcus radiodurans (D50S) in complex with the antibiotic lankamycin (3.2 Å) and a double antibiotic complex of lankamycin and lankacidin C (3.45 Å) have been determined, in continuation of previous crystallographic studies on lankacidin-D50S complex. These two drugs have been previously reported to inhibit ribosomal function with mild synergistic effect. Lankamycin, a member of the macrolide family, binds in a similar manner to erythromycin. However, when in complex with lankacidin, lankamycin is located so that it can form interactions with lankacidin in the adjacent ribosomal binding site. When compared to the well-documented synergistic antibiotics, Streptogramins A and B, the pair of lankacidin and lankamycin bind in similar sites, the peptidyl transferase center and nascent peptide exit tunnel, respectively. Herein, we discuss the structural basis for antibiotic synergism and highlight the key factors involved in ribosomal inhibition.protein exit tunnel | ribosomes

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Section: Discussionmentioning

confidence: 97%

Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit

Belousoff

Shapira

Bashan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Here, we focus only on the structural bases of ribosomal antibiotics binding and their modes of action. The crystallographic structural information provided valuable insights into the common mechanisms of antibiotic function, resistance, and selectivity that are shared by most of the clinically relevant bacteria, but did not show the minor structural differences between different pathogenic bacteria [ 18 ] that may be exploited for addressing species-specific significant differences in antibiotic susceptibility. In this regard, the structures of complexes of antibiotics with ribosomes from two pathogenic bacteria, Escherichia coli [ 7 , 8 , 15 ] and Staphylococcus aureus ( S. aureus ) [ 16 ], were shown to be useful for identification of unique structural motifs.…”

Section: Introductionmentioning

confidence: 99%

Ribosomal Antibiotics: Contemporary Challenges

et al. 2016

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Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of “pathogen-specific antibiotics,” in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification.

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“…Biomaterials‐associated infection is a concern with all biomedical devices that contact tissue and is usually assumed as a given in cases involving, for example, long term percutaneous structures or serious trauma involving large and contaminated wounds. The general problem is being increasingly exacerbated by the growing preponderance of antibiotic resistant bacteria and the concomitant decline of new antibiotic development 13, 14…”

Section: Introductionmentioning

confidence: 99%

Length‐Scale Mediated Differential Adhesion of Mammalian Cells and Microbes

Wang

Subbiahdoss

Swartjes

et al. 2011

Adv Funct Materials

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Surfaces of implantable biomedical devices are increasingly engineered to promote their interactions with tissue. However, surfaces that stimulate desirable mammalian cell adhesion, spreading, and proliferation also enable microbial colonization. The biomaterials‐associated infection that can result is now a critical clinical problem. We have identified an important mechanism to create a surface that can simultaneously promote healing while reducing the probability of infection. Surfaces are created with submicrometer‐sized, non‐adhesive microgels patterned on an otherwise cell‐adhesive surface. Quantitative force measurements between a staphylococcus and a patterned surface show that the adhesion strength decreases significantly at inter‐gel spacings comparable to bacterial dimensions. Time‐resolved flow‐chamber measurements show that the microbial deposition rate dramatically decreases at these same spacings. Importantly, the adhesion and spreading of osteoblast‐like cells is preserved despite the sub‐cellular non‐adhesive surface features. Since such length‐scale‐mediated differential interactions do not rely on antibiotics, this mechanism can be particularly significant in mitigating biomaterials‐associated infection by antibiotic‐resistant bacteria such as MRSA.

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Designer drugs for discerning bugs

Cited by 7 publications

References 20 publications

Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit

Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit

Ribosomal Antibiotics: Contemporary Challenges

Length‐Scale Mediated Differential Adhesion of Mammalian Cells and Microbes

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