Targeting Antibiotic Resistance

Abstract

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled "Combat drug resistance: no action today means no cure tomorrow" triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

Keywords: antibiotic resistance; antibiotics; drug design; medicinal chemistry; structure-activity relationships.

Figure 1

The four resistance acquisition pathways, the four main mechanisms of resistance, and the five main targets for antibiotics.

Figure 2

The mechanism of bacterial translation. Antibacterial targets highlighted.

Figure 3

Structures of the first two oxazolidinones synthesized by Upjohn.

Figure 4

A) Co‐crystal structure of linezolid (1; C green, F purple) in the 50S ribosomal subunit from Haloarcula marismortui (PDB ID: 3CPW). B) A model of linezolid (1) in the 50S ribosomal subunit from H. marismortui that has been methylated by Cfr at A2503Ec. The surface clash is highlighted in red. Escherichia coli numbering in parentheses. Model was generated with Chimera 1.10.1 according to K. J. Shaw et al.14, 35

Figure 5

Structures of tedizolid phosphate, tedizolid, and radezolid compared to linezolid.

Figure 6

Models of tedizolid (4) (C green, F purple) in A) the 50S ribosomal subunit from H. marismortui (PDB ID: 3CPW) and B) the 50S ribosomal subunit from H. marismortui that has been methylated by Cfr. Even with methylation at A2503Ec, tedizolid (4), unlike linezolid, is able to bind to the ribosomal RNA. E. coli numbering in parentheses. Models generated with Chimera 1.10.1 and AutoDock Vina 1.1.2 according to K. J. Shaw et al.14, 16, 35

Figure 7

Overlay of sparsomycin (6) (C orange) and linezolid (1; C green, F purple) in the 50S ribosomal subunit of H. marismortui (PDB IDs: 1M90, 3CPW).

Figure 8

Structures of sparsomycin, linezolid, and molecules developed on the way to radezolid.

Figure 9

Structures of the three macrolides erythromycin, clarithromycin, and azithromycin, as well as the ketolide telithromycin.

Figure 10

Overview of the binding mode of erythromycin (9; C green) to the 50S ribosomal subunit (PDB ID: 1JZY) from Deinococcus radiodurans. The nucleotides are labeled according to D. radiodurans (E. coli in parentheses).

Figure 11

Structures of the ketolides telithromycin and solithromycin.

Figure 12

Overlay of telithromycin (12; C green, PDB ID: 4V7S) and solithromycin (13; C yellow, F purple) in the 50S ribosomal subunit (PDB ID: 4WWW) from E. coli. Nucleotides are labeled using the E. coli numbering system.

Figure 13

Structure–activity relationships of ketolides.

Figure 14

Structures of thiopeptides.

Figure 15

Co‐crystal structure of LFF571 (17; C green) and EF‐Tu (PDB ID: 3U2Q) from E. coli. The carboxylic acid groups of LFF571 are in proximity to Arg223 and Arg262.

Figure 16

Structures of representative tetracycline antibiotics.

Figure 17

Structures of representative glycylcycline and aminomethylcycline antibiotics.

Figure 18

Overlay of tetracycline (21; C yellow; PDB ID: 4V9A) and tigecycline (26; C green, Mg²⁺ ions light brown; PDB ID: 4V9B) bound to the 30S ribosomal subunit (PDB ID: 4V9B) from Thermus thermophilus. Tigecycline makes additional stacking interaction with C1054 compared to tetracycline. T. thermophilus numbering is used for the nucleotides.

Figure 19

Overlay of TetM (blue ribbon; PDB ID: 3J25) and tigecycline (26; C green, Mg²⁺ ions light brown; PDB ID: 4V9B) bound to the 30S ribosomal subunit (PDB ID: 4V9B) from T. thermophilus. The superimposition was generated by means of the cryo‐electron microscopy density map EMD‐2183 of the TetM‐70S complex from E. coli according to Jenner et al. and Dönhöfer et al.96, 99

Figure 20

Structures of typical and atypical aminoglycosides. The aminocyclitol core is highlighted in blue.

Figure 21

Kanamycin A (37; C green) in complex with a decoding A‐site oligonucleotide (PDB ID: 2ESI). A1492 and A1493 are kept in the flipped‐out position by kanamycin A. E. coli numbering is used for the nucleotides.

Figure 22

Co‐crystal structure of kanamycin A (37; C green) and adenylyltransferase ANT(2“)‐Ia (Mg²⁺ ions light brown; PDB ID: 4WQL) from Klebsiella pneumoniae. Kanamycin A is kept in place by a hydrogen‐bonding network.

Figure 23

Structures of sisomicin and amikacin.

Figure 24

Structure of plazomicin and AME modification sites. The HABA chain (blue) blocks modifications at the 3‐N and 2′′‐O positions, the hydroxyethyl chain (red) blocks modifications at the 6′‐N position, and the absence of hydroxy groups at C3′ and C4′ prevents modification at these positions. Only the 2′‐N position remains unblocked to AACs.

Figure 25

Cell wall synthesis. Antibacterial targets are highlighted.

Figure 26

Diagram of the binding of vancomycin to Lipid II sterically prevents the transglycosylation and transpeptidation steps. Key interactions of vancomycin with the d‐Ala‐d‐Ala fragment shown in blue and were identified from co‐crystal structures of vancomycin with analogues of cell‐wall precursors (PDB ID: 1FVM).129

Figure 27

A) Modifications made by the Boger group to vancomycin. Addition of the lipophilic side chain from oritavancin is shown in green; modifications to the carbonyl of residue 4 are shown in purple. B) Dual binding behavior of the amidine functional group.

Figure 28

The structural similarities between the core of β‐lactam antibiotics and the d‐Ala‐d‐Ala terminal sequence of peptidoglycan chains (blue), and the general mechanism of action of transpeptidases (purple) and β‐lactamases (orange).

Figure 29

X‐ray structure of penicillin G (C green) covalently bound via Ser62 to penicillin‐binding protein 4 of E. coli (PDB ID: 2EX8).

Figure 30

Summary of cephalosporin structure–activity and structure‐property relationships.

Figure 31

Structures of cephalosporins.

Figure 32

A) An overview of the two binding sites of ceftaroline (43; C green [allosteric site] and orange [active site]) in PBP2a from S. aureus (PDB ID: 3ZG0). B) Ceftaroline (43; C orange) covalently bound within the active site of PBP2a (gray ribbon, PDB ID: 3ZG0). Once ceftaroline is bound to the allosteric site, the active site opens up in comparison to the closed state (blue ribbon, PDB ID: 4BL2). C) Ceftaroline (43; C green) bound non‐covalently to the allosteric binding site of PBP2a (PDB ID: 3ZFZ).

Figure 33

Monocyclic β‐lactams with the siderophores highlighted in blue.

Figure 34

Comparison of siderophore‐conjugated monocyclic β‐lactam antibiotics. A) Aztreonam (49; C light blue) covalently bound to PBP3 (PDB ID: 3PBS) from P. aeruginosa. The carboxylic acid moiety (C green) of aztreonam engages in polar interactions with Arg489, and the gem‐dimethyl group interacts with the hydrophobic pocket formed by Tyr503, Tyr532, and Phe533. B) X‐ray structure of BAL30072 (47; C light blue) covalently bound to PBP3 (PDB ID: 4OOM) from P. aeruginosa. The siderophore moiety (C purple) of BAL30072 replaces the carboxylic acid and forces Arg489 into a non‐binding orientation. C) The crystal structure of 50 (C light blue) covalently bound to PBP3 (PDB ID: 4WEL) from P. aeruginosa demonstrates optimized binding of the siderophore monocarbam conjugate (siderophore moiety: C purple; carboxylic acid moiety: C green).

Figure 35

The three β‐lactamase inhibitors with β‐lactam cores that are currently in clinical use.

Figure 36

Crystal structure of tazobactam (53; C green) covalently bound via Ser70 to the β‐lactamase SHV‐1 (PDB ID: 2H10) from K. pneumoniae.

Figure 37

The diazabicyclooctane (DBO) non‐β‐lactam inhibitors and similarity with the β‐lactam core (blue).

Figure 38

X‐ray structure of avibactam (54; C green) bound via Ser81 to the β‐lactamase OXA‐24 (PDB ID: 4WM9) from A. baumannii.

Figure 39

Inspiration for and structure of RPX7009.

Figure 40

X‐ray structure of RPX7009 (58; C green, B light magenta) bound to AmpC (PDB ID: 4XUX) from Enterobacter cloacae.

Figure 41

Structure–activity relationships contributing to the development of new boron‐based β‐lactamase inhibitors (60, 61).

Figure 42

Overlay of the EthR crystal structure containing dioxane fragments (C purple; PDB ID: 1T56) and the co‐crystal structure of BDM14500 (62; C green) bound to the transcription factor EthR (PDB ID: 3G1O), both from M. tuberculosis.

Figure 43

Boosters of ethionamide bioactivation.

Figure 44

Co‐crystal structure of tetracycline (21; C green, Mg²⁺ ion light brown) bound to the transcription factor TetR (PDB ID: 2TRT) from E. coli.

Figure 45

Transcription‐factor‐binding molecules for restoring tetracycline susceptibility.