Natural Products as Platforms To Overcome Antibiotic Resistance

Abstract

Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrow-spectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

Figure 1

Representative classes of antibiotics of the modern era, excluding the arsenic-containing antibiotics of the early twentieth century. Color coding corresponds to the mechanisms of action in Figure 3.

Figure 2

Total infections (gray) and deaths (black) in the US associated with various pathogenic bacteria. CRE = carbapenem-resistant enterococci; VRE = vancomycin-resistant enterococci; MDR = multidrug resistant.

Figure 3

Schematic representation of the three major mechanisms of action of widely used antibiotics, also noting the sulfa drugs.

Figure 4

Schematic representation of general antibiotic resistance mechanisms.

Figure 5

Traditional means of generating diverse compound libraries, including combinatorial and semisynthetic approaches.

Figure 6

Innovative strategies in generating diversity through synthesis.

Figure 7

Diverted total synthesis leads to analogs of epothilone B with superior pharmacological characteristics.

Figure 8

Spring’s diversity-oriented synthesis seeking anti-MRSA compounds. MICs in μg/mL.

Figure 9

DOS strategy to access enopeptin analogs. (a) Enopeptin antibiotics as inspiration. (b) Modifications to enopeptin scaffold with biological evaluation (MICs, μg/mL) against Gram-positive bacteria. ND = not determined.

Figure 10

Huigens’ ring distortion strategies to access yohimbine-based bioactive scaffolds.

Figure 11

Crystal structure of erythromycin bound to E. coli ribosome with ribosomal proteins omitted. 30S subunit in yellow, 50S subunit in orange, erythromycin in blue. View down the axis of the nascent peptide exit tunnel, outlined in cyan. Key interactions of erythromycin and telithromycin with the ribosome. Erythromycin is conformationally rigid due to the avoidance of syn-pentane interactions between methyl groups; we also highlight hydrogen bonding across the macrocycle above. Both macrolides hydrogen-bond to A2058 through desosamine; telithromycin makes an additional π-stacking interaction with A752, explaining its enhanced binding affinity. Structures edited in Swiss PDB Viewer and rendered in UCSF Chimera from PDB IDs 4V7U (erythomycin) and 4V7S (telithromycin).

Figure 12

(a) Acid-driven decomposition of erythromycin to spiroketal necessitating drug modification. (b) Semisynthetic macrolides developed from erythromycin with year of FDA approval. (c) Semisynthetic ketolides at various stages in development. *To the best of our knowledge, the company sponsoring cethromycin, Advanced Life Sciences, ceased operations in 2011.

Figure 13

Rationale in designing new fully synthetic macrolides; selected analogs fall into two general categories: ketolides bearing an unsaturated side chain with varying heterocycles, and azaketolides, including an azacethromycin analog.

Figure 14

Crystal structure of tetracycline (2) bound to E. coli ribosome; 50S subunit in orange, 30S subunit in yellow, ribosomal proteins omitted for clarity. Tetracycline shown in blue binding to the A site of the ribosome, which inhibits binding of acyl-amino-tRNA necessary for protein synthesis. On the right, 2 binding to selected residues demonstrating key hydrogen-bonding contacts between the southern ridge of 2, a magnesium ion, and the sugar−phosphate backbone. Images produced in UCSF Chimera, PDB ID 5J5B.

Figure 15

Phylogenetic relationship of semisynthetic tetracycline derivatives and parent natural products with dates of FDA approval. Though tetracycline was first discovered following hydrogenolysis of chlorotetracycline, it was later identified as another streptomycete natural product.

Figure 16

Profiles of total syntheses of tetracyclines.

Figure 17

Schematic comparison of a previous totally synthetic approach to the tetracyclines with Myers’ strategy.

Figure 18

Tetracycline derivatives under development by Tetraphase.

Figure 19

Ring systems and numbering in viridicatumtoxin B (158).

Figure 20

Crystal structure of vancomycin bound to a Lipid II mimic. Below, computational studies demonstrating the decreased binding affinity associated with the VanA phenotype. PDB ID 1VFM.

Figure 21

Biosynthesis of VanA-type Lipid II bearing a D-Lac substitution.

Figure 22

Structures of approved glycopeptides and lipoglycopeptides with year of approval and sourcing. * denotes epivancosamine.

Figure 23

Truncated lipoglycopeptide analogs developed for mechanistic studies by Kahne.

Figure 24

(a) Schematic representation and rationale of target-accelerated combinatorial synthesis. (b) General blueprint of the vancomycin dimer containing a tether through the vancosamine sugars. (c) Optimization of linker makeup and length. MICs in μg/mL.

Figure 25

(a) Design of vancomycin analogs with N-terminal amino acid mutations and (b) biological evaluation. MICs in μg/mL. Gray shading indicates that no comparison can be made relative to the activity of vancomycin against a particular strain.

Figure 26

Boger’s vancomycin aglycon analogs with pocket modifications.

Figure 27

In vitro binding assays of aglycon analogues to peptidoglycan mimics 288 and 289. The ratio indicates x-fold decrease in binding affinities. In vivo MIC assay against E. faecalis BM 4166, expressing VanA, μg/mL.

Figure 28

Boger’s peripheral modifications to the CBP-vancomycin scaffold.

Figure 29

Schematic representation of QS systems in P. aeruginosa. Color scheme: yellow/orange: LasR-mediated; blue: RhlR-mediated; green: promotors; red: repressors. Inspired from refs and . Of particular interest is the regulation of toxins, as shown in the Venn diagram.

Figure 30

(a) Natural and synthetic AHLs; (b) synthetic inhibitors; and (c) agonists of pyocyanin production in PAO1.

Figure 31

PQS, due to its hydrophobicity, is transported between bacteria via membrane vesicles. When delivered to another P. aeruginosa cell (orange), PQS acts as a quorum sensing molecule. When delivered to a foreign species, such as S. aureus (green), PQS is an antibiotic, allowing P. aeruginosa to outcompete other species for valuable resources. Inspired from refs ^, , and . On the right, molecules implicated in the PQS system.

Figure 32

(a) Selected halophenazine analogs by Huigens tested against Gram-positive bacteria with (b) MICs in μM.

Figure 33

Schematic representation of Agr-mediated quorum sensing. Inspired from refs and .

Figure 34

AIPs from S. aureus.

Figure 35

AIPs from S. epidermidis and analogs of 347 with IC₅₀ values against AgrC I, II, and III.

Figure 36

Structure of fidaxomicin, aka lipiarmycin, aka tiacumicin B, an 18-membered macrolide.

Figure 37

Analogs of carolacton synthesized by Kirschning.

Scheme 1

Summary of Key Steps in the First and Only Total Synthesis of Erythromycin A by Woodward

Scheme 2

Summary of Key Steps in Martin’s 1997 Synthesis of Erythromycin B

Scheme 3

Summary of Key Steps in Kang’s 1997 Synthesis of Azithromycin

Scheme 4

Syntheses of Key Intermediates en Route to 14- and 15-Membered Azaketolides by Myers

Scheme 5

Myers’ Completion of Azaketolides 83 and 86 via Identical Endgames

Scheme 6

Andrade’s Total Synthesis of 4-Desmethyl Telithromycin (110)

Scheme 7

Oyelere’s Semisyntheses of Extended-Range Azithromycin Analogs

Scheme 8

Myers’ First-Generation Synthetic Route to AB-Enone 147

Scheme 9

Divergent yet Convergent Approach To Generating Diverse and Unprecedented Tetracycline Scaffolds

Scheme 10

Myers’ 2008 Extension of the DTS Approach To Expand on Leads Identified in 2005 Work

Scheme 11

Nicolaou’s Construction of the Viridicatumtoxin Skeleton

Scheme 12

Total Synthesis of Viridicatumtoxin B and Related Analogs

Scheme 13

Evans’ Preparation of the Left-Hand Tetrapeptide 195

Scheme 14

Preparation of Right-Hand Tripeptide 200, Union with 195, and Completion of the Synthesis

Scheme 15

Nicolaou’s Preparation of Amino Acid Building Blocks

Scheme 16

Nicolaou’s Preparation of Right-Hand Tripeptide 227

Scheme 17

Nicolaou’s Assembly of Left-Hand Tetrapeptide 233 and Construction of the Vancomycin Scaffold

Scheme 18

Endgame toward the Total Synthesis of 201

Scheme 19

Boger’s Synthesis of the Left-Hand Tetrapeptide 265 Optimized for Atropisomeric Efficiency

Scheme 20

Assembly of Vancomycin Aglycon

Scheme 21

Boger’s Diverted Total Synthesis of Methylene Analog 270 via Intermediate 275

Scheme 22

Boger’s Synthetic Diversion of 260 to Thioamide 271 and Amidine 272

Scheme 23

Boger’s Elaboration of Aglycon Analogs to Glycosylated Vancomycin Analogs and CBP-Derivatives

Scheme 24

(a) Total Synthesis of Promysalin by Wuest; (b) Analogs of Promysalin Bearing Simple Modifications around the Pyrrolidine, Salicylate, and Myristate Portions; (c) Chimeric Promysalin Analogs Derived from the Fatty Acid Derivatives Lyngbic Acid and Hermitamides A and B

Scheme 25

Kirschning’s 2012 Synthesis of Carolacton (369): (a) Preparation of Macrocycle Precursor 378; (b) Synthesis of Side Chain Precursor 387 and NHK Coupling; (c) Macrocyclization and Endgame

Scheme 26

Phillips’ and Wuest’s Total Synthesis of Carolacton (369): (a) Preparation of Macrocycle 400; (b) Synthesis of Side Chain Precursor 406; (c) Esterification, Macrocycle, and Endgame; (d) Bioactive Simplified Analogs of Carolacton Accessed through Wuest’s DTS Approach

Scheme 27

(a) Related Natural Products Bromoageliferin (415) and Oroidin (416) and Analogs Derived Therefrom by Melander. (b) Representative Synthesis of 417; CAGE (418) Was Synthesized in an Analogous Manner from the Appropriate Epimer of 420