Tackling antibiotic resistance: a dose of common antisense?

Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, London NW9 5EQ, UK.
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.31). 12/2008; 63(2):225-9. DOI: 10.1093/jac/dkn467
Source: PubMed


Resistance to antimicrobial agents undermines our ability to treat bacterial infections. It attracts intense media and political interest and impacts on personal health and costs to health infrastructures. Bacteria have developed resistance to all licensed antibacterial agents, and their ability to become resistant to unlicensed agents is often demonstrated during the development process. Conventional approaches to antimicrobial development, involving modification of existing agents or production of synthetic derivatives, are unlikely to deliver the range or type of drugs that will be needed to meet all future requirements. Although many companies are seeking novel targets, further radical approaches to both antimicrobial design and the reversal of resistance are now urgently required. In this article, we discuss 'antisense' (or 'antigene') strategies to inhibit resistance mechanisms at the genetic level. These offer an innovative approach to a global problem and could be used to restore the efficacy of clinically proven agents. Moreover, this strategy has the potential to overcome critical resistances, not only in the so-called 'superbugs' (methicillin-resistant Staphylococcus aureus, glycopeptide-resistant enterococci and multidrug-resistant strains of Acinetobacter baumannii, and Pseudomonas aeruginosa), but in resistant strains of any bacterial species.

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    • "In the Americas, Europe, and parts of Africa and Asia, MRSA is the predominant multi-drug resistant microbe, making it a global concern of escalating importance in terms of cost and patient safety [3]. Combating MRSA with new pharmaceutical agents offers only short-term solutions; unconventional approaches may comprise a more effective solution to drug-resistant infectious microbes [4]. "
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    • "Expressed antisense technology has been used to target a range of bacterial genes, including those involved in DNA exchange (Wang and Kuramitsu, 2005), central metabolism (Greenberg et al., 2010), and antibiotic resistance (Ramirez et al., 2013). The antisense molecule is typically complementary to the RBS of the target mRNA, to facilitate steric block of translation initiation (Woodford and Wareham, 2009). A positive correlation between the length of an asRNA and the degree of target gene regulation has been reported for E. coli (Tatout et al., 1998). "
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    ABSTRACT: The rise and spread of antibiotic resistance is among the most severe challenges facing modern medicine. Despite this fact, attempts to develop novel classes of antibiotic have been largely unsuccessful. The traditional mechanisms by which antibiotics work are subject to relatively rapid bacterial resistance via mutation, and hence have a limited period of efficacy. One promising strategy to ameliorate this problem is to shift from the use of chemical compounds targeting protein structures and processes to a new era of RNA-based therapeutics. RNA-mediated regulation (riboregulation) has evolved naturally in bacteria and is therefore a highly efficient means by which gene expression can be manipulated. Here, we describe recent advances toward the development of effective anti-bacterial therapies, which operate through various strategies centered on RNA.
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    • "Antibiotic resistance is a globally interrelated public health problem, the threat of which is ever increasing. Dispersion of large mobile genetic elements carrying multiple resistance determinants coupled with dissemination of successful clones have been chronicled in most bacterial species [1], [2]. Locally, antibiotic exposure selects and promotes the evolution of multidrug resistant (MDR) bacteria, [3], [4] and movement of people and transport of food facilitate their worldwide dispersion [5]. "
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