Chapter 27 : Evolution of Antibiotic Resistance by Hypermutation

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Antibiotic resistance may be regarded as the paradoxical consequence of the success of antibiotic therapy. Bacteria develop antibiotic resistance in two main ways: horizontal gene transfer and mutation in different chromosomal loci. The Mycobaterium tuberculosis species has to acquire antibiotic resistance by mutational events exclusively. Mutation is the raw material of evolution and is the ultimate source of heritable variation on which natural selection acts. The importance of recombination in the evolution of bacterial pathogens has become increasingly apparent. Recombination probably mediates genetic change in all bacterial species and is likely to have been crucial in allowing bacteria to avoid the immune response, in distributing among the population genes that increase virulence or transmission between hosts, and in providing increased resistance to antibiotics. A pathogen microorganism may be the paradigmatic example of a relationship between the stable hypermutation/hyperrecombination status and antibiotic resistance acquisition. This is the case of Streptococcus pneumoniae, where transformation and recombination seem to be the major sources of genetic variability. Microorganisms harboring an antibiotic-resistance mechanism, acquired either by horizontal transfer or mutation, will be positively selected in the presence of the antibiotic. It has been found that environmental and physiological stress conditions can transiently increase the mutation rate in bacteria. A number of studies strongly suggest a possible association between bacteria with high mutation rates and antibiotic-resistance acquisition.

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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Image of Figure 1.
Figure 1.

Model for the activity of MMR in Escherichia coli. The MutS protein homodimer recognizes and binds specifically to base-base mispairing represented here as bulky triangles (a,b). This complex, by using the energy of the hydrolysis of two ATP molecules, makes a DNA loop (c). The MutL protein homodimer is then recruited, associates with this loop, and activates the endonuclease MutH (c). Activated MutH protein produces a nick in the unmethylated newly synthesized strand, which is assumed to contain the incorrect base (c). Afterwards, the nicked DNA is unbound by UvrD (helicase II) activity (d) and the cleaved strand is subjected to exonuclease degradation. The kind of exonuclease utilized in the degradative process depends on whether MutH cuts the DNA on the 5′ side of the mismatch (ExoVII or RecJ, which degrade DNA in the 5′ → 3′ direction) or the 3′ side (ExoI or ExoX, which degrade DNA in a 3′ → 5′ direction). Here, for simplicity, only one of these processes has been represented. DNA synthesis, mediated by PolIII, and DNA ligation, mediated by DNA ligase, produce a double DNA molecule free of the initial error (e). Finally, the new strand is also methylated (m) in the adenine residue in the sequence GATC by DAM methylase (f). This scheme is based on many others found in the literature, particularly from P. Modrich (Modrich, 1991).

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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Image of Figure 2.
Figure 2.

Scheme of the SOS system describing the main molecular events that occur during the canonical SOS system induction process in E. coli. Under noninduction conditions (e.g., normal growth conditions), the cellular levels of the LexA SOS repressor are sufficient to lock a switch OFF system state. The silencing of gene SOS expression is mediated by the LexA repressor through their binding as a dimer to SOS boxes situated in the promoter region of SOS genes. For simplicity, only 4 of the 40 SOS genes have been represented. The detention of DNA replication originated by, for instance, DNA damage, generated a stalled replication fork. Single-stranded DNA (ssDNA) produced by the stalled fork is a molecular distress signal allowing the nucleation of the RecA monomer protein around the ssDNA. This process induces to the formation of a RecA filament. The interaction of ssDNA-RecA promotes the appearance of the RecA* coprotease activity. This RecA* activated molecular species promotes the autocleavage of the LexA repressor. LexA is a transcriptional regulator composed of two structurally defined domains, an N-terminal DNA-binding domain and a C-terminal dimerization domain. The cleavage in the Ala-84-Gly-85 peptide bond, situated within the hinge region that connects the two domains, liberates these two domains, thus inactivating its negative regulatory activity. This molecular inactivating process decreases the cellular level of LexA, which in turn liberates the gene SOS repression, switching the system to ON. Between the induced novel SOS functions are included two error-prone DNA polymerases, PolIV and PolV. Whereas PolIV does not require any additional processes for activation, the PolV (a heterotrimer UmuD’2UmuC) requires autocleavage of UmuD, also promoted by RecA*. The TLS (translesion synthesis) promoted by PolIV and PolV permit bypassing of the DNA lesion. Other DNA repair functions, e.g., excision repair (UvrABC) and Holliday resolution junctions (RuvAB), are also induced. Finally, when the ssDNA disappears (or the DNA damage is repaired), the level of RecA* decreases and DNA replication restarts; consequently, the level of LexA repressor increases, taking the SOS system to the OFF state.

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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Image of Figure 3.
Figure 3.

Closed circle for antibiotic resistance development (see text).

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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