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After the discovery and commercial introduction of antibiotics, it was soon noticed that usually treatable infections were not affected by the treatment with antibiotics and had adapted mechanisms of resistance. Alexander Fleming predicted that too low frequent doses of penicillin would lead to the development of penicillin resistance. Surprisingly, bacterial resistance towards penicillin was actually noticed before it was made widely available to use, after a while, it was finally recognised that there should be some antibiotic control, as the use of penicillin and other

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antibiotics were not restricted by any means (Hellen et al., 2015). Antibiotic resistance is a result

of the evolutionary pressure that bacteria undergo, resistance occurs for all antibiotics after their clinical administration, and there is a limit to the number of antibiotic substances which fulfil all pharmacokinetics demands. Because of this, much of the antibiotic work done after the 1960s was focused on chemically modifying existing antibiotics to make them more potent to resistant pathogens and to improve pharmacokinetics properties. Recently, researchers have tried to find a new antibiotic candidate from natural products (e.g. medicinal plants) in a hope to meet the health sector demands (Davies & Dorothy, 2010).

There are many methods by which bacteria can become resistant to antibiotics. The current scale of the problem and the number of resistances against drugs across different classes is unprecedented. Resistance can be caused by a variety of mechanisms and it can be summarised as: (i) the presence of an enzyme that inactivates the antibiotic agent, bacteria can produce enzymes that are capable of adding different chemical groups to antibiotics that prevents binding between the antibiotic and its target in the bacterial cell; (ii) the presence of an alternative

enzyme for the enzyme that is inhibited by the antibiotic agent, for instance, Staphylococcus

aureus can acquire the resistance gene mecA and produce a new penicillin-binding protein, the new penicillin-binding protein has low affinity to β-lactam antibiotics and results resistant to the drugs, (iii) a mutation in the antibiotic agent’s target which results changes in the composition or structure of the target in the bacterium and stop the antibiotic from interacting with the target. Alternatively, the bacteria can add different chemical groups to the target structure, in this way shielding it from the antibiotic; (iv) destroy the antibiotic through enzymes that can inactivate antibiotics. One obvious example is β-lactamase that destroys the active component (the β-lactam ring) of penicillin. Later, bacteria developed extended-spectrum β- lactamases and become a major problem, due to the ability of destroying a wide spectrum of β-

lactam antibiotics; (v) reduced uptake of the antibiotic agent,bacteria achieve that by decrease

the permeability of the membrane that surrounds the bacterial cell which make it more difficult to pass through; and (vi) efflux pumps, bacteria can produce pumps that are localised in their membrane or cell wall. In some cases, mutations in the bacterial DNA can make the bacteria

produce more pumps to reduce the antibiotic concentration inside the bacterial cell (Fluit et al.,

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Figure 2.2: Schematic diagram of major antibiotic mechanisms of resistance (Gullberg, 2014).

At least seventeen different classes of antibiotics have been produced to date. Unfortunately, for each one of these classes at least one mechanism of resistance has developed over the years. In fact, in some cases these bacteria have been able to develop simultaneous resistance to two or more antibiotic classes, making the treatment of infections caused by these microorganisms extremely difficult, very costly and in many cases associated with high morbidity and mortality (Alanis, 2005).

Antibiotic resistance can be divided into natural resistance and acquired resistance. Natural resistance means that the bacteria are intrinsically resistant, an example of this can be due to increased efflux activity, a mechanism responsible for moving out toxic substances and antibiotics outside the cell. Acquired resistance refers to bacteria that are usually sensitive to antibiotics, but are liable to develop resistance. Acquired resistance is often caused by mutations in chromosomal genes, or by the acquisition of mobile genetic elements, such as plasmids or transposons, which carry the antibiotic resistance genes. (Katrijn and Arthur 2009).

20 It is important to have a good understanding of the molecular basis by which development of resistance occurs, because it allows us to develop new approaches to managing the infections caused by these bacteria and to create new strategies for the development of new treatments against these bacteria (Sefton, 2002). In most cases of bacterial resistance, changes in the genetic composition of the susceptible bacteria take place, either via a mutation or by the introduction of new genetic information. The expression of these genetic changes within the cell result in changes to one or more biological mechanism of the affected bacteria and ultimately determines the specific type of resistance that the bacteria develops, resulting in a myriad of possible

biological forms of resistance (Figure 2.3). (Dzidic et al., 2008).

Figure 2.3: Schematic diagram showsbiochemical and genetic aspects of antibiotic resistance

mechanisms in bacteria. Adapted from (Dzidic et al., 2008).

The resistance among various microbial species (infectious agents; e.g., bacteria, fungi, virus, and parasite) to different antimicrobial drugs has emerged as a cause of public health threat all over the world, at a terrifying pace. One such bacterial pathogen is methicillin-resistant

Staphylococcus aureus (MRSA), it has for several years been increasingly spreading at inpatient and outpatient health care facilities worldwide. This organism is capable of causing a range of infections from skin and soft tissue infections to more life threatening illnesses such as

21 pneumonia, bacteremia and surgical site infections (Landecker, 2015). The next section will focus on MRSA, as it comes a huge clinical burden that is causing great public and political concern, specially that the current treatments proved to be inactive.