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The Complexity of Molecular Targeting by Antibiotics Acting on the Ribosome | OMICS International
ISSN: 2161-0711
Journal of Community Medicine & Health Education

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The Complexity of Molecular Targeting by Antibiotics Acting on the Ribosome

Dimitrios L Kalpaxis*

Department of Biochemistry, School of Medicine, The University of Patras, Greece

*Corresponding Author:
Dimitrios L Kalpaxis
Department of Biochemistry
School of Medicine, The University of Patras, 6504-Patras, Greece
Tel: +302610996124

Received date: December 27, 2012; Accepted date: December 27, 2012; Published date: December 29, 2012

Citation: Kalpaxis DL (2012) The Complexity of Molecular Targeting by Antibiotics Acting on the Ribosome. J Community Med Health Educ 2:e114. doi:10.4172/2161-0711.1000e114

Copyright: © 2012 Kalpaxis DL. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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X-ray crystallography and Cryo-E microscopy have revealed numerous cavities in bacterial ribosomes, not existing in human cytosolic ribosomes [1]. Some of them present features favorable to the binding of antibiotics that disrupt protein synthesis. This is reflected in the large number of ribosome-targeting antibiotics in current clinical use. Nevertheless, the extensive use of antibiotics for over 60 years has led inevitably to the spread of resistant strains. An additional layer of complexity is associated with the high conservation of the structure of functional sites within ribosomal RNA, in particular between prokaryotic and mitochondrial translation machinery, which implies limitations with respect to selectivity and toxicity [2]. Any new strategies to manage antibiotic resistance and reduce side-effects can be addressed through accelerating the development of new drugs and improving safe and appropriate use of antibiotics.

Targeting of Ribosomes by Antibiotics

Binding of antibiotics to the ribosome is a prerequisite for their action. Most of the studies investigating the binding of antibiotics (A) to the ribosome (R) have been based so far on the assumption that this interaction can be expressed by a fast equilibrium of the form R + A ?RA, giving emphasis on the thermodynamic control of the interaction [3,4]. Bacteria have evolved several elegant solutions to ridding the ribosome of antibiotics, e.g., by lowering the intracellular concentration A via pumping out the antibiotics and hindering their uptake [5], or by increasing the dissociation of the RA complex via reprogramming the target structure [6] and destroying the antibiotic warhead [7]. Therefore, the efforts for development of new antibiotics have been often oriented to approaches tending to exploit the thermodynamic control of the antibiotic-ribosome interaction, thus overlooking the kinetic control of the binding process. However, several lines of evidence have increasingly recognized the significance of the binding kinetics, especially the duration that an antibiotic stays in complex with the ribosome [8-10]. When the association and dissociation rate constants are sufficiently small, the interaction between ribosome and antibiotic equilibrates slowly and the degree of translation inhibition is time-dependent [11,12]. As revealed by kinetic studies [13-16], NMR and modeling studies [17,18], and footprinting analysis at discrete time-intervals following mixing the ribosome with the drugs [13,16,19], access of some antibiotics to the ribosome occurs through a two-step mechanism, R + A ? RA ? R*A. The first step of the binding process, rapidly established, involves a low-affinity site. Subsequently, slow conformational changes in the target and/or in the ligand cause shifting of the antibiotic into a high-affinity pocket, from which the antibiotic dissociates slowly. Because of the cohesive long-lasting binding of the drug to the ribosome, such antibiotics are less vulnerable to the activity of efflux pumps and exhibit strong post-antibiotic effects (PAE), i.e., persistent antibacterial effects after removal of the inhibitory drug [20], and they are poor inducers of methyltransferases that modify the target site [21].

Another problem, usually met in preclinical studies, is associated with the fact that much of the work toward unveiling the molecular features of the antibiotic-ribosome interaction and the mechanisms of resistance has been performed, using model organisms. Nevertheless, it has been already recognized that conclusions drawn from such organisms cannot safely extrapolated to other pathogenic bacteria; species-specific differences in the drug binding site may dramatically influence the efficacy of an antibiotic [2,22]. Therefore, the application of high-throughput Screening methods for assessing the efficacy of natural or natural-like compounds on clinical isolates of interest should be a major challenge for future work.


Although the need for novel antibacterials has been greater than ever in the face of widespread resistance, since the year 2000 only four new classes of antibiotics have been discovered [23]. The reasons of the decline in antibiotic discovery are mainly non-scientific, but clearly economical; targeting an antibiotic to a resistant organism may not improve the chances of a company, because of the limited market size. If the non-prudent use of antibiotics continues, unfortunately new mechanisms of resistance against novel drugs will be emerging. The incidence of bacterial resistance represents a serious problem not only to patients, but also to global healthcare systems. Health Authorities have to promote surveillance and stewardship networks to educate physicians and the general public in avoiding inappropriate use of antibiotics and reducing transmission of antibiotic resistant strains through effective infection-control systems.


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