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Chapter 4 : Antibiotics That Block Peptidoglycan Assembly and Integrity

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Abstract:

This is the first of five consecutive chapters that take up the mechanisms of action of major classes of antibiotics, based on the nature of their killing targets at the surface of or within pathogenic bacterial cells. This chapter builds directly on the structure, composition, function, and biosynthetic pathways of the peptidoglycan (PG) layer of bacterial cell walls elaborated on in chapter 3. In that chapter, we noted in brief some of the molecules that act on biosynthetic enzymes in the cytoplasmic phase of PG assembly, such as cycloserine and fosfomycin, that have established but rather minor niches among current antibacterial therapeutics. The focus in this chapter is on the major classes of cell wall-targeting antibiotics that for decades have seen widespread clinical use for the treatment of life-threatening bacterial infections (Fig. 4.1).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Figures

Image of Figure 4.0
Figure 4.0

Time course microscope images of an cell over a 2-hour period after treatment with cephalexin, a cephalosporin β-lactam antibiotic. (a) Prior to treatment with cephalexin, the takes on a normal rod shape. (b) At 34 minutes after treatment, the cell begins to elongate. (c) After 70 minutes, the filamentation is more pronounced and a bulge begins to form. (d) Bulge formation ends. (e) Image taken right before cell lysis. (f) Image taken directly after lysis begins. (Adapted from Daniel Kahne [Yao et al., 2012] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.1
Figure 4.1

Classes of approved β-lactam and glycopeptide antibiotics that target bacterial PG.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.2
Figure 4.2

(a) Chemical structure of penicillin N as determined by X-ray crystallography. (b) Enzymatic deacylation of penicillin N gives the aminopenicillin core that can be chemically derivatized into the suite of penicillin antibiotics utilized over the past 70 years. (c) The penicillins are biosynthetic precursors to a second class of bicyclic β-lactam antibiotics, the cephalosporins. (Three-dimensional image of isopenicillin N generated using PyMOL v1.7 and PDB ligand ID A14.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.3
Figure 4.3

The carbapenem bicyclic structure represents a third class of β-lactam antibiotics. Thienamycin, the first naturally occurring carbapenem to be discovered, was formulated into clinically useful imipenem through chemical modification of the exocyclic amine. Eventually the scaffold was further evolved to create members of subsequent carbapenem generations, including meropenem and ertapenem.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.4
Figure 4.4

Five classes of β-lactam antibiotics with a representative naturally occurring member from each class. The core β-lactam structure is shown in black, and the variable side chains are shown in red.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.5
Figure 4.5

(a, b) Hydrolysis of the penicillin β-lactam ring gives penicilloic acid, which is deactivated and devoid of antibiotic activity. (c) In place of water, serine transpeptidases use an active-site serine residue to react with activated esters (β-lactams) and other amides (X = NHR) or esters (X = OR), forming an acyl enzyme intermediate with subsequent deacylation through attack by water (esterases, amidases, and lactamases) or an amine (transamidases).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.6
Figure 4.6

Autoradiograph of [C]penicilloyl proteins of separated on denaturing gel electrophoresis. (Reprinted from Spratt [1975] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.7
Figure 4.7

Enzymatic action of ,-carboxypeptidases and ,-transpeptidases on the -Ala--Ala C terminus of PG.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.8
Figure 4.8

Structural similarity between the -Ala--Ala terminus of the PG peptidyl stem (a) and penicillins (b).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.9
Figure 4.9

,-Transpeptidases cross-link PG on the millisecond time scale, allowing for rapid strengthening of the bacterial cell wall. Inhibition of TPases by β-lactam substrate mimics of -Ala--Ala leads to long-lived covalent acyl enzyme adducts with physiological half-lives on the order of hours. Inhibition of TPases on this time scale leads to a compromised cell wall and ultimately cell lysis.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.10
Figure 4.10

X-ray crystal structures of apo-PBP1a from (a) and PBP1b from bound to moenomycin (b). The TPase, TGase, oligosaccharide-binding (OB) domain, and protein-protein interaction domain are highlighted.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.11
Figure 4.11

Structures of the PBP1-selective β-lactam antibiotic cephaloridine (a), the PBP2-selective β-lactam mecillinam (b), and the PBP3-selective cephalosporin cephalexin (c). PBP-selective β-lactam antibiotics have helped reveal the distinct roles of individual PBPs in assembling the cell wall and determining cell shape.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.12
Figure 4.12

Biosynthesis of the penicillin and cephalosporin core structures originates from three simple amino acid precursors. Deacetylation of the amino side chain followed by chemical derivatization allows for the semisynthesis of a wide swath of β-lactam antibiotics with unique antibacterial and pharmacokinetic properties.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.13
Figure 4.13

Classes of β-lactam antibiotics that have been commercialized. Classes are displayed on the horizontal axis. Generations are displayed from top to bottom on the vertical axis.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Vignette 4.1
Vignette 4.1

Uncoupling of transpeptidase and transglycosylase action arising from penicillin-mediated block of TPase activity leads to enhanced activity of lytic transglycosidase in a futile metabolic cycle.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.14
Figure 4.14

Chemical structures of imipenem, a carbapenem β-lactam antibiotic; and cilastatin, a renal dipeptidase inhibitor. This combination therapy (trade name Primaxin) improves the half-life of imipenem, which is prone to hydrolysis by renal dipeptidase in the kidneys.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.15
Figure 4.15

(a) Many β-lactams fall victim to bacterial resistance through the action of β-lactamase enzyme-mediated hydrolysis of the square lactam ring. (b) Coadministration of a β-lactam with a β-lactamase inhibitor can resensitize β-lactamase-producing bacteria and restore potent inhibition of TPases. (c) Several β-lactam–β-lactamase inhibitor combination therapies have found clinical success. Shown here are penicillin–β-lactamase inhibitor combinations amoxicillin-clavulanate (Augmentin), ampicillin-sulbactam (Unasyn), and piperacillin-tazobactam (Zosyn). β-Lactam antibiotics are shown in black and β-lactamase inhibitors in red.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.16
Figure 4.16

The moenomycin family of lipopolysaccharides produced by is the lone example of potent TGase inhibitors. Moenomycin shares many structural similarities to lipid II (hydrophobic lipid chain, phosphate linkage, polysaccharide backbone, and polyamides).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.17
Figure 4.17

(a) X-ray crystal structure of neryl-moenomycin (shown in red) bound to the TGase active site of PBP1a from (PDB 3D3H). (b) A close look at the interactions between moenomycin and the active-site TGase residues reveals an intricate network of noncovalent interactions responsible for the observed nanomolar inhibitory concentrations.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.18
Figure 4.18

Vancomycin binds to the -Ala--Ala termini of the pentapeptide strands in un-cross-linked PG, weakening the structural integrity of the cell wall.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.19
Figure 4.19

(a) Vancomycin is a structurally complex glycopeptide produced by soil actinomycetes. (b) X-ray structure of the vancomycin-lipid II complex. The chemical scaffold of vancomycin is exquisitely tuned to selectively bind lipid II through an intricate hydrogen bonding network made possible by the cup-like conformation of vancomycin (generated using PDB entry 1FVM). The sequestration of scarce lipid II is detrimental to assembly of the PG framework, leaving the cell wall compromised.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.20
Figure 4.20

Next-generation vancomycin analogs have been developed and approved for human use to extend the lifetime of this important class of antibiotics. Important structural differences from the parent vancomycin scaffold are highlighted in red.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.21
Figure 4.21

(a) Cartoon representation of nisin showing the A to E ring systems with bridging sulfurs. (b) Chemical structure of nisin, a lantibiotic, with lanthionine units highlighted in red.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.22
Figure 4.22

Nisin binds with nanomolar affinity to lipid II and aggregates in cell membranes in pore-like structures composed of eight nisin molecules and four lipid II molecules, causing membrane perturbation. The high affinity of nisin for lipid II is a result of the A ring acting as a “phosphate cage,” as determined by high-resolution NMR and X-ray structures. (Image of the nisin-pyrophosphate cage reprinted from Hsu et al. [2014] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Vignette 4.2
Vignette 4.2

Conversion of the teicoplanin family natural product A40926 by two synthetic steps to the commercialized antibiotic dalbavancin.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Vignette 4.3
Vignette 4.3

Elongating chains of spherical . Credit: US Centers for Disease Control and Prevention.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Vignette 4.4
Vignette 4.4

Methicillin-resistant (MRSA) has been termed a “professional pathogen”. Credit: Janice Haney Carr/CDC/Jim Biddle; CDC-PHIL ID#9994.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.23
Figure 4.23

Lipid II is sequestered by vancomycin and nisin each targeting distinct ends of the lipid II scaffold. (Adapted from Walsh and Wencewicz [2014] with permission.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.24
Figure 4.24

(a) Structure of ramoplanin, a nonribosomal peptide that sequesters lipid II. (b) Ramoplanin's solution conformation resembles an amphipathic U-shape with a clear binding cleft for lipid II. Interaction of ramoplanin with the pyrophosphate of lipid II is critical. The hydrogen bonding network between ramoplanin and lipid II is complex and is still being mapped. (Figure generated using PyMOL from PDB file 1DSR.)

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.25
Figure 4.25

Structures of other known lipid II-sequestering agents. Mannopeptimycins are nonribosomal peptides from streptomycetes, lysobactin (also known as katanosin B) is a nonribosomal peptide from , and plusbacin A is a lipopeptidolactone of pseudomonal origin.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.26
Figure 4.26

Defensin proteins, such as plectasin, directly bind both lipid I and lipid II in a highly specific fashion. Shown here is the X-ray structure of plectasin (PDB 3E7U).

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.27
Figure 4.27

(a) Bacitracin is a dodecapeptidyl lactam from . The thiazoline plays a critical role in metal binding to form high-affinity bridging complexes with bactoprenol-PP exposed on the extracellular face of the lipid membrane. (b) The bacitracin (gray)–bactoprenol-PP (black) complex, as shown in this X-ray structure, forms a tight complex with bound Zn (salmon color) coordinated by the thiazoline ring (red), and the remainder of the bacitracin nonribosomal peptide backbone is involved in tight coordination of a sodium atom (red) to complete a finely tuned pyrophosphate cage. This unique mechanism of action blocks phosphatase conversion to bactoprenol-P for cycling back to the cytoplasm, shutting down cell wall assembly.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.28
Figure 4.28

The antibiotics daptomycin and friulimicin B are both Ca-dependent antibiotics but operate in different ways. Friulimicin B binds bactoprenol-P, while daptomycin (described in chapter 5) is a membrane disruptor.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.29
Figure 4.29

(a) Tsushimycin is another calcium-dependent antibiotic that (b) dimerizes in the presence of Ca. Tsushimycin binds tightly to bactoprenol-P at the extracellular space, prevents flipping of bactoprenol back to the cytoplasm, and thus blocks PG assembly at the transition from the cytoplasmic phase to the membrane-anchored phase.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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Image of Figure 4.30
Figure 4.30

Peptidyl nucleoside antibiotics block the formation of lipid I by inhibiting MraY on the cytoplasmic face of the lipid membrane. This unique mode of action blocks transition from the cytoplasmic to membrane phase of PG assembly, and it is made possible by the unique structures of these antibiotics mimicking the lipophilic bactoprenol-P and UDP-MurNAc-pentapeptide substrates. See Fig. 3.24 for X ray of MraY with superimposed tunicamycin.

Citation: Walsh C, Wencewicz T. 2016. Antibiotics That Block Peptidoglycan Assembly and Integrity, p 68-100. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch4
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