Bacteria are said to be resistant to an antimicrobial drug if the maximal level of the agent that can be achieved in vivo or tolerated by the host does not halt their growth. Some organisms are inherently resistant to an antibiotic, for example, because they lack the target of the antimicrobial agent. However, microbes that are normally responsive to a particular drug may develop resistance through spontaneous mutation or by acquisition of new genes followed by selection. Some strains may even become resistant to more than one antibiotic by acquisition of genetic elements that encode multiple resistance genes. soft tissue infections caused by this organism.

A. Genetic alterations leading to drug resistance Acquired antibiotic resistance involves mutation of existing genes or the acquisition of new genes.

 1. Spontaneous mutations in DNA: Chromosomal alteration may occur by insertion, deletion, or substitution of one or more nucleotides within the genome. The resulting mutation may per sist, be corrected by the organism, or be lethal to the cell. If the cell survives, it can replicate and transmit its mutated properties to progeny cells. Mutations that produce antibiotic-resistant strains can result in organisms that proliferate under selective pressures such as in the presence of the antimicrobial agent. An example is the emergence of rifampin-resistant Mycobacterium tuberculosis when rifampin is used as a single antibiotic.

 2. DNA transfer of drug resistance: Of particular clinical concern is resistance acquired due to DNA transfer from one bacterium to another. Resistance properties are often encoded on extrachromosomal plasmids, known as R, or resistance, factors. DNA can be transferred from donor to recipient cell by processes including transduction (phage mediated), transformation, or bacterial conjugation.

B. Altered expression of proteins in drug-resistant organisms Drug resistance may be mediated by several different mechanisms, including an alteration in the antimicrobial drug target site, decreased uptake of the drug due to changes in membrane permeability, increased efflux of the drug, or the presence of antibiotic-inactivating enzymes.

 1. Modification of target sites: Alteration of an antimicrobial agent's target site through mutation can confer resistance to one or more related antibiotics. For example, S. pneumoniae resistance to β-lactam drugs involves alterations in one or more of the major bacterial penicillin-binding proteins, resulting in decreased binding of the antimicrobial to its target.

2. Decreased accumulation: Decreased uptake or increased efflux of an antimicrobial agent can confer resistance because the drug is unable to attain access to the site of its action in sufficient concentrations to inhibit or kill the organism. For example, gram-negative organisms can limit the penetration of certain agents, including β-lactam antibiotics, tetracyclines, and chloramphenicol, as a result of an alteration in the number and structure of porins (channels) in the outer membrane. Also, expression of an efflux pump can limit levels of a drug that accumulate in an organism. For example, transmembrane proteins located in the cytoplasmic membrane actively pump intracellular antibiotic molecules out of the microorganism (Figure 1). These drug efflux pumps for xenobiotic compounds have a broad substrate specificity and are responsible for decreased drug accumulation in multidrug-resistant cells. The efflux pumps may be encoded on chromosomes and plasmids, thus contributing to both intrinsic (natural) and acquired resistance, respectively. As an intrinsic mechanism of resistance, efflux pump genes allow bacteria expressing them to survive a hostile environment (for example, in the presence of antibiotics), which allows for the selection of mutants that overexpress these genes. Being located on transmissible genetic elements as plasmids or transposons is also advantageous for the microorganism insofar as it allows for the easy spread of efflux genes between distinct species.

Fig1. Schematic representation of an efflux pump.  

3. Enzymatic inactivation: The ability to destroy or inactivate the antimicrobial agent can also confer resistance to microorganisms. Examples of antibiotic-inactivating enzymes include 1) β-lactamases that hydrolytically inactivate the β-lactam ring of penicillins, cephalosporins, and related drugs; 2) acetyltransferases that trans fer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides; and 3) esterases that hydrolyze the lactone ring of macrolides.

مواضيع ذات صلة

Agents Used to Treat Bacterial Infections

Antimicrobial Susceptibility Testing and Therapy for Bacillus and Similar Organisms

Penicillin- resistant bacteria

المضادات الميكروبية التي ترتبط الى الوحدة الرايبوسومية الكبيرة 50S

المضادات المكروبية التي ترتبط الى الوحدة الرايبوسومية الصغيرة 30S

اختبارات الحساسية للمضادات الحيوية

أوجه الشبه والاختلاف في تركيب جدار الخلية الموجبة - لغرام والسالبة – لغرام التي تؤثر على الحساسية للمضادات الحيوية

الأهداف التي تصيبها المضادات الحيوية في البكتيريا

المضادات الحيوية للبكتيرية Antibacterial Antibiotics

Ethambutol

Pyrazinamide

Isoniazid