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Chapter 10 : Antibiotic Resistance: Modification or Destruction of the Antibiotic

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Antibiotic Resistance: Modification or Destruction of the Antibiotic, Page 1 of 2

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Abstract:

In this chapter, we take up three cases of clinically important antibiotics in which modification or destruction of the antibiotic is a principal route to neutralization/inactivation of the antibiotic class (Fig. 10.0) (Walsh, 2000). The first deals with enzymatic hydrolysis of the β-lactam warhead in penicillins, cephalosporins, and carbapenems. The second deals with modification of each of the two streptogramin components of the Synercid combination, reflecting two different approaches to render the polyketide versus the nonribosomal peptide scaffold of streptogramin A and streptogramin B components unrecognizable by their intended ribosome targets. The third example involves the suite of enzymes known to modify sites in the tricyclic framework of aminoglycosides. Fourteen distinct sites on those antibiotics are targeted by three different kinds of group transfer enzymes that use either ATP or acetyl coenzyme A (acetyl-CoA), thermodynamically activated substrates of primary metabolism, to derivatize oxygen or nitrogen atoms. The addition of charged (phosphate, AMP) and/or bulky (AMP, acetyl) groups to the aminoglycosides disrupts high-affinity binding to the 16S rRNA sites on the 30S ribosomal subunit.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Figures

Image of Figure 10.0
Figure 10.0

Augmentin is a β-lactam (shown in blue)/β-lactamase inhibitor (shown in red) drug combination (amoxicillin/clavulanate) that represents a clinical solution to antibiotic resistance via antibiotic modification. The red β-lactamase inhibitors take out the antibiotic hydrolyzing lactamases in the exterior face of the membrane and allow the blue antibiotics to pass intact to their PBP targets.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.1
Figure 10.1

The highly strained β-lactam ring is shown in red to emphasize the 90° bond angles, in this case in the antibiotic ampicillin.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.2
Figure 10.2

The hydrolysis of ampicillin to ampicillinoic acid has a favorable free energy change Δ of reaction of –14.5 kJ/mol (Kishore et al., 1994).

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.3
Figure 10.3

The lifetimes of the acyl enzymes control the differential fates of hydrolytic processing of the -Ala--Ala peptidoglycan (PG) substrate (a) compared to processing of penicillin by the transpeptidase (TPase) (b) and the active-site serine classes of β-lactamases (BL) (c).

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.4
Figure 10.4

The peptidoglycan fragment is imported to the cytoplasm in order to remove the transcriptional repression of , which leads to the secretion of the AmpC β-lactamase into the periplasm.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.5
Figure 10.5

Subclasses of β-lactamases have evolved from a common precursor PBP. Class A, C, and D are members of the serine hydrolase superfamily, while class B has members that use active-site metal ions for catalyzing hydrolysis of lactam substrates. Mw, molecular weight. (Adapted from Massova and Mobashery [1998] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.6
Figure 10.6

The direction of attack of the active-site water on the β-lactam ring is distinct in class A versus class C lactamases; the water comes from above in class A and below in class C. In contrast, the bound water molecules at the active site of the ,-peptidase are not oriented for sufficient attack on the strained β-lactam, accounting for the longer lifetime of the acyl enzyme intermediate. (Adapted from Massova and Mobashery [1998] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.7
Figure 10.7

The catalytic cycle for the bi-zinc class B metallo-β-lactamase. In contrast to class A, C, and D lactamases, no acyl enzyme intermediates are formed.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.8
Figure 10.8

TEM-1 isolated from can hydrolyze the β-lactam ring of the penicillins and early cephalosporins. TEM-121, an ESBL, was isolated from an strain found in the clinic in 2004 and demonstrated the ability to also hydrolyze late-generation cephalosporins, monobactams, and some β-lactamase inhibitors. TEM-121 has five point mutations from TEM-1 (Glu104Lys, Arg164Ser, Ala237Thr, Glu240Lys, and Arg244Ser), all of surface residues.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Vignette 10.1
Vignette 10.1

Aspergillomarasmine, a known fungal metabolite, uses its four side chain carboxylates to chelate the active site iron in metallo-β-lactamases, offering a scaffold for further optimization of activity against this class of penicillin- and cephalosoporin-hydrolyzing enzymes.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.9
Figure 10.9

Upregulation of the Bla enzymes occurs when the two-component signaling system comes into contact with a β-lactam antibiotic. (Step 1) A molecule of β-lactam antibiotic binds to the active-site serine of the BlaR­­1 enzyme on the outside of the outer membrane. (Step 2) A conformational change occurs that releases the BlaR2 on the inside of the cellular envelope. (Step 3) BlaR2 cleaves BlaI off of the DNA to allow for the transcription of downstream resistance genes. (Step 4) The β-lactamase BlaZ is produced from the downstream genes. (Step 5) BlaZ is transported out of the cell, and the signal sequence is cleaved off of the protein. (Step 6) The BlaZ β-lactamase starts hydrolyzing incoming antibiotics (Blas et al., 2014).

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.10
Figure 10.10

Thienamycin inhibits β-lactamases by undergoing an olefin isomerization once it is at the acyl enzyme level. The acyl enzyme partitions between hydrolysis and enamine-to-imine isomerization, yielding a much more stable acyl enzyme. The enzyme piles up in this state, which accounts for the long half-life of inhibition.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.11
Figure 10.11

Clavulanate (a) and sulbactam (b) are mechanism-based inactivators of the serine class of β-lactamases. They both go partway through the catalytic cycles, and the acyl enzyme intermediates are set up for fragmentation and ultimate inactivation by cross-linking. The oxygen and sulfone functional groups in the five-membered rings predispose the molecules to fragmentation (Brown et al., 1996).

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.12
Figure 10.12

Combination β-lactam–β-lactamase inhibitor antibiotic therapies currently being used in the clinic and in clinical trials.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.13
Figure 10.13

The combination of avibactam and ceftazidime has recently been approved for clinical use as Avycaz. Avibactam, as a γ-cyclic urea, is an unusual β-lactamase inhibitor. The acyl enzyme does not partition in the hydrolysis direction, but will reclose to the starting avibactam.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.14
Figure 10.14

In dalfopristin and virginiamycin, sites of inactivating O-acetylation are shown in red.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.15
Figure 10.15

Inactivation of quinupristin and related streptogramins by Vgb lyase fragmenting the cyclic depsipeptide at the lactone linkage by an elimination mechanism.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.16
Figure 10.16

(a) Three types of enzymatic modifications that inactivate aminoglycoside scaffolds. (b) The different regiochemistries for acetylation (Ac), phosphorylation (PO), and nucleotidylation (NT) on the different OH and NH substituents of the aminoglycosides.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.17
Figure 10.17

Structures of first-generation antibiotics kanamycin, gentamicin, and tobramycin, along with the semisynthetic derivative amikacin.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.18
Figure 10.18

Pattern of phosphorylation and acetylation of kanamycin-deactivating enzymes. APH, aminoglycoside phosphorylation; AAC, aminoglycoside acetylation. (Kanamycin numbering obtained from Llano-Sotelo et al. [2002].)

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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Image of Figure 10.19
Figure 10.19

The natural product sisomicin can be converted through chemical steps to the semisynthetic neoaminoglycoside plazomicin with metabolic sites of deactivation blocked.

Citation: Walsh C, Wencewicz T. 2016. Antibiotic Resistance: Modification or Destruction of the Antibiotic, p 198-218. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch10
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