1887

Chapter 12 : Resistance via Target Modification

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Resistance via Target Modification, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819316/9781555819316_ch12-1.gif /docserver/preview/fulltext/10.1128/9781555819316/9781555819316_ch12-2.gif

Abstract:

The strategy of bacteria of modifying an essential target so that it is still functional for its normal physiologic role but less sensitive or desensitized to the action of a specific antibiotic is complementary to the strategy discussed in chapter 10, in which it is the antibiotic that is modified. In principle, if target modification to reduce affinity for an antibiotic, say of the enzyme DNA gyrase for fluoroquinolones (Fig. 12.1a), does not hamper that enzyme's catalytic efficiency, then building in the resistance is more effective. The alternative is to wait until an antibiotic such as a β-lactam shows up in the neighborhood and starts to wreak havoc on the peptidoglycan assembly machinery before lactamase gene induction occurs to turn on the hydrolysis of the lactam warhead. The presumption that modifying the essential cellular targets to antibiotic insensitivity has no fitness cost may not be fully justified, and it has been reasoned that some targets are more difficult to modify than others.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 12.0
Figure 12.0

MRSA and VRE: two bacterial pathogens that become clinically resistant by target alteration. Images courtesy of (top) National Institute of Allergy and Infectious Diseases (CDC-PHIL #18167) and (bottom) CDC/Pete Wardell (CDC-PHIL #12803).

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.1
Figure 12.1

(a) The GyrAB tetramer known as DNA Gyrase in complex with two antibiotics shown as red space filling models: ciprofloxacin bound to the GyrA subunits and novobiocin bound to the GyrB subunits. (b) Quinolone-resistant mutants in the GyrA subunit of bacterial DNA gyrase. Ciprofloxacin and known resistance-conferring point mutations in GyrA (Ser-84 to Ala, Ser-85 to Pro, Glu-88 to Lys) are shown in green. (b) Coumarin-resistant mutants in the GyrB subunit of bacterial DNA gyrase. Novobiocin and known resistance-conferring point mutations in GyrA (Asp-89 to Gly, Ser-128 to Leu) are shown in green. The full DNA gyrase model was generated by fitting PDB files 2XCT (full dimeric GyrA bound to ciprofloxacin and DNA) and 1EI1 (full dimeric GyrB) to PDB file 4GFH (full dimeric GyrA-GyrB DNA gyrase from ). The ATP-binding domains of the GyrB were then replaced with the domains from GyrB bound to novobiocin using PDB file 4URO. All referenced mutations refer to amino acid numbering in the GyrA,B proteins. All images were created using PyMOL.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.2
Figure 12.2

SAM-dependent methylation of bases or sugars in both 16S and 23S rRNA is a common mechanism for resistance to several kinds of ribosome-targeting antibiotics. SAH, S-adenosyl-homocysteine.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.3
Figure 12.3

Modification of the lipid A portion of LPS in the outer membrane can occur by introduction of either of two cationic groups: PmrEF attaches 4-amino--arabinose in phosphodiester linkage, while PmrC attaches an ethanolamine instead.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.4
Figure 12.4

Modification of lipid A by 4-amino--arabinose on the external surface of the cell requires coordinated regulation and transport of the aminoarabinose building block.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.5
Figure 12.5

Generic structure of the lysyl ester of bacterial dimeric cardiolipin (composed of two phosphatidylglycerol monomers). Lysinylation occurs by the action of the MprF enzyme. The overall charge has gone from dianionic to monocationic, causing resistance to daptomycin, which targets negative charges decorating the surface of the cell.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.6
Figure 12.6

The two-component system for the regulation of MprF is triggered by cationic peptides. This causes a downstream lysinylation of phosphatidylglycerol and dimeric cardiolipin ( Fig. 12.5 ), conferring resistance to the cationic peptides that caused the cascade in the first place.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.7
Figure 12.7

The membrane-embedded MprF protein facilitates both a lysinylation event and a transmembrane flip, presenting cationic antibacterial agents with the positive charges of the lysine moiety and conferring resistance.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.8
Figure 12.8

The esterification of polymeric teichoic acid glycerol units () and ribitol units () at the C position via the enzymatic -alanine thioester DltA. It reduces the overall negative charge of the polyanionic network, conferring resistance to cationic antibiotics both by charge repulsion and by increasing the physical density of the network.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.9
Figure 12.9

(a) An illustration of polyanionic wall and lipoteichoic acids (red) in the cell envelope of Gram-positive bacteria. (b) An illustration of the increased density (and thus decreased permeability) of the polyanionic network upon alanylation of wall teichoic acid and lipoteichoic acid backbone units. Cryo-electron microscope images of bacterial cell walls in (d) wild-type (WT) and (c) mutant ( deleted) . The decreased density of the matrix can be plainly seen when the cell is not able to reduce the charge of its teichoic acids, resulting in more light being let through the cell. (Images in panels c and d modified from Saar-Dover et al. [2012] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.10
Figure 12.10

Graph showing the percent incidence of VRE (compared to total enterococci infections) from 1988 to 2003 (Infectious Diseases Society of America, 2004).

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.11
Figure 12.11

(a) VanR and VanS act as a two-component signaling pathway for the entire gene cluster. This results in vancomycin resistance via VanHAX and a positive feedback loop for expression of VanRS. (b) The combined actions of VanHAX lead to replacement of the terminal -Ala--Ala dipeptide with a terminal -Ala--lactate depsipeptide (ester) linkage.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.12
Figure 12.12

The hydrogen bond network of vancomycin to lipid II--Ala--Ala (left) and lipid II--Ala--Lac (right).

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.13
Figure 12.13

VanHAX and MurF act to produce the modified UDP-muramyl pentapeptide with a -Ala--lactate terminus that has 1,000-fold-lower affinity for vancomycin than the wild-type pentapeptide.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.14
Figure 12.14

The final stage of peptide cross-linking from the -Ala--Lac terminus generates the identical cross-linked peptidoglycan (PG) strands found in the wild-type PG layer. The lactate has thus been a disappearing protective group to keep the lipid II species from being captured by vancomycin.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.15
Figure 12.15

Ceftobiprole (top) and ceftaroline (bottom), two fifth-generation cephalosporins.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.16
Figure 12.16

X-ray structure of MRSA PBP2a with two molecules of ceftaroline bound. The one in the active site is the ring-opened acyl enzyme at serine 403. The one in the allosteric site has the β-lactam intact. (Image created using PyMOL from PDB entry 3ZFZ.)

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 12.17
Figure 12.17

(a) Oxadiazole (O'Daniel et al., 2014), (b) 1,2,4-triazolo[1,5-]pyrimidine (Wang et al., 2015), and (c) quinazolin-4-one (Bouley et al., 2015) heterocyclic inhibitors of MRSA PBP2a. The cocomplex of the quinazolin-4-one and crystalline PBP2a shows residency of the ligand in the allosteric site. (Image created using PyMOL from PDB entry 4CJN.)

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Vignette 12.1
Vignette 12.1

Synthetic modification of the chlorobiphenyl derivative of vancomycin aimed at reducing the lone pair repulsion between the amide carbonyl of residue four and the ester oxygen of d-Ala-d-Lac intermediates has led Boger and colleagues to an amidine scaffold that has activity against both wild type and vancomycin resistant forms of (VRE).

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Vignette 12.2
Vignette 12.2

The methicillin-resistant PBP2a of MRSA strains has now been shown to have an allosteric site that serves as a second binding region for lactams such as ceftaroline. Combination of ceftaroline with a second lactam antibiotic can increase affinity for recognition of the active site of PBP2a.

Citation: Walsh C, Wencewicz T. 2016. Resistance via Target Modification, p 230-251. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch12
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555819316.ch12

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error