The continued appearance of multi-drug resistant bacterial strains is increasingly limiting the effectiveness of current drugs. Therefore, the development of new antibiotics or antimicrobial agents is necessary if the problem is to be kept within limits. The discovery and development of new compounds that either block or circumvent resistance mechanisms could improve the containment, treatment and eradication of these strains (Oluwatuyi et al., 2004). Sibanda & Okoh (2007) therefore suggested that targeting and blocking resistance processes could be an attractive approach. The various strategies that could serve as possible means to combat antibiotics resistance are summarized below:
Use of bacteriophages.
The structure of a typical myovirus bacteriophage
Viruses that infect bacteria and replicates within them are called bacteriophages. A phage kills the host bacterium by causing lysis of the cell wall (bacteriolysis). As bacteriophages have evolved to kill their bacterial hosts efficiently, they represent potent antibacterial agents that could be explored to control infectious diseases caused by bacterial pathogens. Parisien et al., (2007) reported that although the use of phage for the treatment of bacterial infections (phage therapy) was developed at the same time as the antibiotics, their use was limited due to the specificity of the phage treatment. All tailed phages have double-standed DNA (dsDNA) as genome and they encode endolysins (virulolysins) that enable them to lyse the cell walls (Young et al., 2000; Bernhardt et al, 2002). Some lytic phages use the virolysin-holin system to hydrolyse the cell wall while others use a single lytic factor to compromise the strength of the cell wall. Virolysin is a muralytic enzyme that hydrolyses peptideglycan in bacterial cell wall and holin is a small peptide that oligomerizes in the membrane to form disruptive membrane lesions (Ugorcakova and Bukovska, 2003). Disruption of the cell wall can also happen in the adsorption stage if a high multiplication of infection (MOI) is used (Tarahovsky et al., 1994). In this case, a substantially large number of phage particles attach to the same bacterial cell. Filamentous phages that do not cause lysis of the bacterial cell wall cannot be used directly for phage therapy. For this purpose, they are genetically modified. Hagens & Blasi (2003) and Hagens et al. (2004) demonstrated this by genetically replacing the transportation gene involved in the extrusion of the phage particle with a restriction enzyme. The phages lost the ability to extrude from the bacterial cells but then acquired endonuclease activity. The researchers were of the opinion that genetically modified phages would be effective anti-infection agents and the release of membrane-associated endotoxin will also be reduced in the process.
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There are a growing number of evidences that shows that phages can be used for clinical treatment or prevention of infectious diseases caused by both Gram-positive and Gram-negative bacteria (Bull et al., 2002; Stone, 2002). Phages have also been shown to be effective for the elimination of food poisoning pathogens such as Listeria monocytogenes, Campylobacter jejuni and Salmonella spp. (Greer, 2005). In 2006, the FDA approved the use of six viruses that were specifically designed to eradicate strains of L. monocytogens for the treatment of ready to eat meat (Petty et al., 2007). In the future, phage therapy will become a very effective alternative after extensive and careful selection of appropriate phages.
Advantages of Phage therapy:
It is effective against multidrug- resistant pathogenic bacteria and substitution of the normal microbial flora does not occur because the phages kill only the targeted pathogenic bacteria.
It can respond quickly to the appearance of phage-resistant bacteria mutants because the freguency of phage mutation is significantly higher than that of bacteria
The side-effects are very rare (Matsuzaki et al., 2005).
Disadvantage of phage therapy:
Phages may pick up toxins and virulence factors and horizontally transfer them from one bacterium to another (Brussow et al., 2004; Skurnik and Strauch, 2006). When a prophage cuts its genome from the bacterial genome, it can erroneously integrate some part of the bacterial genome into its own genome.
The bacterium may acquire resistance to phages either by acquiring a restriction modification system that degrades the injected phage nucleic acid or loss of a gene essential for phage multiplication or assembly (Skurnik and Strauch, 2006).
2. Use of Plant Extracts.
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A number of in vitro studies have reported the use of plant extracts in combination with antibiotics resulting in significant reduction in the minimum inhibitory concentration (MIC) of the antibiotics against some resistant strains (Betoni et al., 2006; Darwish et al., 2002; Al-hebshi et al., 2006). In these combination studies, it is speculated that the inhibition of drug efflux could be responsible for the synergistic interactions between plant extracts and antibiotics (Lewis & Ausubel, 2006). In a study conducted by Marquez et al., (2005), incorporation of sub-inhibitory concentrations of Ciprofloxacin with the crude chloroform extracts of Jatropha elliptica resulted in increase in the activity of the extract when assayed against NorA (efflux pump)-expressing S. aureus. Inhibition of the efflux pump resulted in the accumulation of the antibiotic inside the bacterial cell, consequently increasing access to its target sites.