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Targets for Combating the Evolution of Acquired Antibiotic Resistance.

Culyba MJ, Mo CY, Kohli RM - Biochemistry (2015)

Bottom Line: This recognition underscores the importance of understanding how such genetic changes can arise.We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets.We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

View Article: PubMed Central - PubMed

ABSTRACT
Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

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Targets ofthe SOS pathway. (A) Structure of the SOS sensor, RecA,shown as a filament (PDB entry 3CMV), with alternating monomers colored darkor light blue. The ssDNA is shown as red spheres. The panel belowis a close-up of the ATP binding pocket (PDB entry 1XMS), a site that couldbe targeted. (B) Shown is dimeric LexA, bound to SOS box DNA (PDBentry 3JSO),with individual monomers colored green and yellow. The C-terminalprotease domain (CTD) is connected to the N-terminal DNA binding domain(NTD) by a structurally unresolved linker (dashed line). In the self-cleavagemechanism, LexA undergoes a large conformational change in its C-terminaldomain between inactive (red sticks, PDB entry 1JHC) and active states(purple sticks, PDB entry 1JHE) that positions the cleavage loop within the activesite, adjacent to the Ser/Lys dyad. The overlaid active and inactiveconformations are shown in the bottom panel. (C) Shown is a representativeY-family polymerase, Dpo4, an error-prone polymerase, bound to DNA(PDB entry 1JX4). Unlike high-fidelity T7 polymerase, shown for comparison (PDBentry 1T7P),Dpo4 possesses a more open, exposed catalytic site, which reducesthe selectivity for the incoming nucleotide, colored green.
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fig4: Targets ofthe SOS pathway. (A) Structure of the SOS sensor, RecA,shown as a filament (PDB entry 3CMV), with alternating monomers colored darkor light blue. The ssDNA is shown as red spheres. The panel belowis a close-up of the ATP binding pocket (PDB entry 1XMS), a site that couldbe targeted. (B) Shown is dimeric LexA, bound to SOS box DNA (PDBentry 3JSO),with individual monomers colored green and yellow. The C-terminalprotease domain (CTD) is connected to the N-terminal DNA binding domain(NTD) by a structurally unresolved linker (dashed line). In the self-cleavagemechanism, LexA undergoes a large conformational change in its C-terminaldomain between inactive (red sticks, PDB entry 1JHC) and active states(purple sticks, PDB entry 1JHE) that positions the cleavage loop within the activesite, adjacent to the Ser/Lys dyad. The overlaid active and inactiveconformations are shown in the bottom panel. (C) Shown is a representativeY-family polymerase, Dpo4, an error-prone polymerase, bound to DNA(PDB entry 1JX4). Unlike high-fidelity T7 polymerase, shown for comparison (PDBentry 1T7P),Dpo4 possesses a more open, exposed catalytic site, which reducesthe selectivity for the incoming nucleotide, colored green.

Mentions: RecA isa highly conserved∼38 kDa protein that plays a critical role in homologous recombinationand also acts to stimulate LexA self-cleavage.43 Structurally, monomeric RecA consists of three domainswith a central core RecA fold that is flanked by smaller regulatorydomains.44 These monomers can form largenucleoprotein filaments on ssDNA (Figure 4A),which can extend across thousands of base pairs via cooperative oligomerizationmediated by the core RecA fold.45 FilamentousRecA has a deep helical groove that envelopes, stretches, and unwindsthe bound DNA, preparing it for homology searching and subsequentDNA strand exchange. The core RecA fold binds ATP at the monomer–monomerinterface (Figure 4A).44 While only binding of ATP is required for filament formation andsimple DNA strand exchange reactions, RecA also catalyzes ATP hydrolysis,which is important for filament depolymerization as well as some specifictypes of recombination activities.43


Targets for Combating the Evolution of Acquired Antibiotic Resistance.

Culyba MJ, Mo CY, Kohli RM - Biochemistry (2015)

Targets ofthe SOS pathway. (A) Structure of the SOS sensor, RecA,shown as a filament (PDB entry 3CMV), with alternating monomers colored darkor light blue. The ssDNA is shown as red spheres. The panel belowis a close-up of the ATP binding pocket (PDB entry 1XMS), a site that couldbe targeted. (B) Shown is dimeric LexA, bound to SOS box DNA (PDBentry 3JSO),with individual monomers colored green and yellow. The C-terminalprotease domain (CTD) is connected to the N-terminal DNA binding domain(NTD) by a structurally unresolved linker (dashed line). In the self-cleavagemechanism, LexA undergoes a large conformational change in its C-terminaldomain between inactive (red sticks, PDB entry 1JHC) and active states(purple sticks, PDB entry 1JHE) that positions the cleavage loop within the activesite, adjacent to the Ser/Lys dyad. The overlaid active and inactiveconformations are shown in the bottom panel. (C) Shown is a representativeY-family polymerase, Dpo4, an error-prone polymerase, bound to DNA(PDB entry 1JX4). Unlike high-fidelity T7 polymerase, shown for comparison (PDBentry 1T7P),Dpo4 possesses a more open, exposed catalytic site, which reducesthe selectivity for the incoming nucleotide, colored green.
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fig4: Targets ofthe SOS pathway. (A) Structure of the SOS sensor, RecA,shown as a filament (PDB entry 3CMV), with alternating monomers colored darkor light blue. The ssDNA is shown as red spheres. The panel belowis a close-up of the ATP binding pocket (PDB entry 1XMS), a site that couldbe targeted. (B) Shown is dimeric LexA, bound to SOS box DNA (PDBentry 3JSO),with individual monomers colored green and yellow. The C-terminalprotease domain (CTD) is connected to the N-terminal DNA binding domain(NTD) by a structurally unresolved linker (dashed line). In the self-cleavagemechanism, LexA undergoes a large conformational change in its C-terminaldomain between inactive (red sticks, PDB entry 1JHC) and active states(purple sticks, PDB entry 1JHE) that positions the cleavage loop within the activesite, adjacent to the Ser/Lys dyad. The overlaid active and inactiveconformations are shown in the bottom panel. (C) Shown is a representativeY-family polymerase, Dpo4, an error-prone polymerase, bound to DNA(PDB entry 1JX4). Unlike high-fidelity T7 polymerase, shown for comparison (PDBentry 1T7P),Dpo4 possesses a more open, exposed catalytic site, which reducesthe selectivity for the incoming nucleotide, colored green.
Mentions: RecA isa highly conserved∼38 kDa protein that plays a critical role in homologous recombinationand also acts to stimulate LexA self-cleavage.43 Structurally, monomeric RecA consists of three domainswith a central core RecA fold that is flanked by smaller regulatorydomains.44 These monomers can form largenucleoprotein filaments on ssDNA (Figure 4A),which can extend across thousands of base pairs via cooperative oligomerizationmediated by the core RecA fold.45 FilamentousRecA has a deep helical groove that envelopes, stretches, and unwindsthe bound DNA, preparing it for homology searching and subsequentDNA strand exchange. The core RecA fold binds ATP at the monomer–monomerinterface (Figure 4A).44 While only binding of ATP is required for filament formation andsimple DNA strand exchange reactions, RecA also catalyzes ATP hydrolysis,which is important for filament depolymerization as well as some specifictypes of recombination activities.43

Bottom Line: This recognition underscores the importance of understanding how such genetic changes can arise.We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets.We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

View Article: PubMed Central - PubMed

ABSTRACT
Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.

Show MeSH