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Target modification

Because antimicrobial drugs have very specific targets, structural changes to those targets can prevent drug binding, rendering the drug ineffective. Through spontaneous mutations in the genes encoding antibacterial drug targets, bacteria have an evolutionary advantage that allows them to develop resistance to drugs. This mechanism of resistance development is quite common. Genetic changes impacting the active site of penicillin-binding proteins (PBPs) can inhibit the binding of β-lactam drugs and provide resistance to multiple drugs within this class. This mechanism is very common among strains of Streptococcus pneumoniae , which alter their own PBPs through genetic mechanisms. In contrast, strains of Staphylococcus aureus develop resistance to methicillin ( MRSA ) through the acquisition of a new low-affinity PBP, rather than structurally alter their existing PBPs. Not only does this new low-affinity PBP provide resistance to methicillin but it provides resistance to virtually all β-lactam drugs, with the exception of the newer fifth-generation cephalosporins designed specifically to kill MRSA. Other examples of this resistance strategy include alterations in

  • ribosome subunits, providing resistance to macrolides, tetracyclines, and aminoglycosides;
  • lipopolysaccharide (LPS) structure, providing resistance to polymyxins ;
  • RNA polymerase, providing resistance to rifampin ;
  • DNA gyrase, providing resistance to fluoroquinolones;
  • metabolic enzymes, providing resistance to sulfa drugs , sulfones , and trimethoprim ; and
  • peptidoglycan subunit peptide chains, providing resistance to glycopeptides .

Target overproduction or enzymatic bypass

When an antimicrobial drug functions as an antimetabolite, targeting a specific enzyme to inhibit its activity, there are additional ways that microbial resistance may occur. First, the microbe may overproduce the target enzyme such that there is a sufficient amount of antimicrobial-free enzyme to carry out the proper enzymatic reaction. Second, the bacterial cell may develop a bypass that circumvents the need for the functional target enzyme. Both of these strategies have been found as mechanisms of sulfonamide resistance . Vancomycin resistance among S. aureus has been shown to involve the decreased cross-linkage of peptide chains in the bacterial cell wall, which provides an increase in targets for vancomycin to bind to in the outer cell wall. Increased binding of vancomycin in the outer cell wall provides a blockage that prevents free drug molecules from penetrating to where they can block new cell wall synthesis.

Target mimicry

A recently discovered mechanism of resistance called target mimicry involves the production of proteins that bind and sequester drugs, preventing the drugs from binding to their target. For example, Mycobacterium tuberculosis produces a protein with regular pentapeptide repeats that appears to mimic the structure of DNA. This protein binds fluoroquinolones , sequestering them and keeping them from binding to DNA, providing M. tuberculosis resistance to fluoroquinolones. Proteins that mimic the A-site of the bacterial ribosome have been found to contribute to aminoglycoside resistance as well. D.H. Fong, A.M. Berghuis. “Substrate Promiscuity of an Aminoglycoside Antibiotic Resistance Enzyme Via Target Mimicry.” EMBO Journal 21 no. 10 (2002):2323–2331.

Questions & Answers

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Every time someone flushes a toilet in the apartment building, the person begins to jumb back automatically after hearing the flush, before the water temperature changes. Identify the types of learning, if it is classical conditioning identify the NS, UCS, CS and CR. If it is operant conditioning, identify the type of consequence positive reinforcement, negative reinforcement or punishment
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Skinner skipped the whole unconscious phenomenon and rather emphasized on classical conditioning
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Source:  OpenStax, Microbiology. OpenStax CNX. Nov 01, 2016 Download for free at http://cnx.org/content/col12087/1.4
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