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Alternative therapeutic strategies to fight bacterial infections

Leila Mousavifar

Department of Chemistry, University of Quebec in Montreal, PO Box 8888, Succ.Centre-Ville, Montreal, Quebec H3C 3P8, Canada

INRS-Institut Armand-Frappier, University of Quebec, 531 boul. Prairie, Laval, Quebec, H7V 1B7, Canada

E-mail : aa

Rene Roy

Department of Chemistry, University of Quebec in Montreal, PO Box 8888, Succ.Centre-Ville, Montreal, Quebec H3C 3P8, Canada

INRS-Institut Armand-Frappier, University of Quebec, 531 boul. Prairie, Laval, Quebec, H7V 1B7, Canada

Glycovax Pharma Inc., 424 Guy, Suite 202, Montreal, Quebec, H3J 1S6, Canada

DOI: 10.15761/FDCCR.1000115

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Introduction

In spite of the large arsenal of antibiotherapies that have help humanities fighting bacterial infections, we are still facing diseases, hospitalization, and death caused by pathogenic agents [1-8]. The advent of the first sulfa drugs in the mid-thirties has launched almost a century of race toward the discoveries of new therapeutic agents by the pharmaceutical industries. The development of the Gram +ve linezolid in 2000 as the first family members of oxazolidinones as well as the Gram-negative lipopeptide antibiotic daptomycin, first discovered by Eli Lilly in 1980 but commercialized in the US in 2003 (23 years gap) have successfully lifted the long innovation gap in the medicinal chemistry era (Figure 1). Ceftaroline, a member of the fifth-generation cephalosporins discovered in 2010 is known to be particularly active against methicillin resistant Staphylococcus aureus (SARM), thus marking the beginning of alternative weapons against this particularly resilient infectious agent.

Figure 1. Development and bacterial resistance pattern of current antibiotics [9]

The advent of medicinal chemistry has allowed the relatively fast discoveries of diverse families of antibiotics working under a wide range of bactericidal or bacteriostatic mechanisms. Unfortunately, bacteria have similarly developed a plethora of defense mechanisms that include: (a) active efflux and sequestration of antibiotics by protein binding; (b) deactivation by enzymatic modification; (c) modification of antibiotic receptors; (d) metabolic bypass of the inhibited reaction; (e) overproduction of the antibiotic targets [9,10].

Since the discoveries of a plethora of therapeutics antibacterial agents, working on more or less similar mechanisms, scientists developed several additional strategies encompassing alternative mechanisms (Table 1). They ranged from cell wall destructions through polycationic entities such as polypeptides and nanoparticles [11,12]; bacterial starving by blocking nutrients input [13]; blocking genes and proteins expressions through siRNA [14]; triggering immune responses by vaccines directed against cell wall components such as capsular polysaccharides, etc. [15,16]. This last approach has been particularly successful in eradicating bacterial infections caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenza type b and so on [17-19].

Table 1. List of alternative therapies against bacterial infections and their mechanism of action

Strategy

Therapeutic agent

Action mechanism

References

1

Nanoparticles

Blocking biofilm formation

12

2

Quoring sensing

Blocking bacterial communication and biofilms

20

3

Siderophore

Enzyme co-factors

21

4

Polycationic peptides

Membrane disruption

11

5

Polycationic NPs

Membrane disruption

20

6

Phytochemicals

Varied

22

7

Repurposing anticancer drugs

Varied

23

8

Vaccines

Antibody-directed bacterial antigens

15-19

9

Antisense oligonucleotides

Inhibition of gene expression

14

10

Peptide Nucleic Acids (PNA)

Inhibition of gene expression

24

11

Transition metals (ex. Silver cations)

Inner membrane disruption

13,25

12

Innate immunity

Macrophage stimulation through TLRs

26

13

Adaptive immunity

Antibody-antibiotic conjugates

27

14

Phage display

Bacterial membrane lysis

28

15

Carbohydrate analogs

Inhibition of carbohydrate processing enzymes

29

16

Carbohydrates

Inhibition of adhesion

30

17

Pilicides

Inhibition of pili formation

38

Of particular interest was the discovery that numerous bacteria express carbohydrate-binding proteins called lectins as virulence factors [31]. In these cases, the bacterial infection is initiated by a carbohydrate-protein recognition process (adhesion) from which the lectins bind to glycoconjugate receptors (glycoproteins, glycolipids) on the host cells (Figure 2). The ensuing steps include the release of deadly toxins and biofilm formation. Amongst these, Pseudomonas aeruginosa, uropathogenic E. coli, several Shigella species, and Burkholderia cenocepacia are representative examples. The case of uropathogenic E. coli infections (UPECs) is particularly well documented because the lectins responsible for the host cell adhesion are known and their structures fully characterized by X-ray crystallography [32]. The E. coli FimH lectin has led to intensive medicinal chemistry efforts that ultimately allowed the discovery of small molecule inhibitors that recently successfully passed clinical Phase 1 [33,34].

Figure 2. Blocking bacterial adhesion by carbohydrate anti-adhesives [33a]

Actually, the proof of principle that clearly demonstrated the first examples of inhibition of bacterial adhesion by carbohydrates was obtained through the pioneering activities of Sharon et al. [35]. For instance, recent investigations showed the direct consequences of exposing carbohydrate ligands such as carbohydrate additives and α-D-mannopyranoside antagonists between uropathogenic E. coli CFT073 bound to human 5637 bladder epithelial cells in vitro (Figure 3) [36-38]. The binding of green fluorescent protein-labelled E. coli strain (CFT073-GFP) could be efficiently inhibited in the presence of low concentration of the sugar as shown by fluorescence microscopy. In addition, there are growing demonstrations that the effect of mannopyranoside antagonists can alter the binding of various uropathogenic E. coli strains in microarray settings including human tissues. Hence, the therapeutic value of identifying potent sugar antagonists against adherent invasive E. coli strains represents an important goal in our arsenal of new drug development.

Figure 3. (Top panel): Adherence of E. coli to epithelial cells in the presence of sucrose (A) and mannose (B); adapted [36] (Bottom panel): Effect of type 1 fimbriae on adherence of uropathogenic E. coli to human bladder epithelial cells in vitro (C) and inhibition of binding in the presence of methyl α-D-mannopyranoside using fluorescence microscopy (D) adapted [37]

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Editorial Information

Editor-in-Chief

Gian Maria Pacifici
University of Pisa, Italy

Article Type

Research Article

Publication history

Received: September 13, 2018
Accepted: October 12, 2018
Published: October 17, 2018

Copyright

©2018 Mousavifar L. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Mousavifar L (2018) Alternative therapeutic strategies to fight bacterial infections. Frontiers Drug Chemistry Clinical Res 2: DOI: 10.15761/FDCCR.1000115

Corresponding author

Mousavifar L

Department of Chemistry, University of Quebec in Montreal, PO Box 8888, Succ.Centre-Ville, Montreal, Quebec H3C 3P8, Canada

Table 1. List of alternative therapies against bacterial infections and their mechanism of action

Strategy

Therapeutic agent

Action mechanism

References

1

Nanoparticles

Blocking biofilm formation

12

2

Quoring sensing

Blocking bacterial communication and biofilms

20

3

Siderophore

Enzyme co-factors

21

4

Polycationic peptides

Membrane disruption

11

5

Polycationic NPs

Membrane disruption

20

6

Phytochemicals

Varied

22

7

Repurposing anticancer drugs

Varied

23

8

Vaccines

Antibody-directed bacterial antigens

15-19

9

Antisense oligonucleotides

Inhibition of gene expression

14

10

Peptide Nucleic Acids (PNA)

Inhibition of gene expression

24

11

Transition metals (ex. Silver cations)

Inner membrane disruption

13,25

12

Innate immunity

Macrophage stimulation through TLRs

26

13

Adaptive immunity

Antibody-antibiotic conjugates

27

14

Phage display

Bacterial membrane lysis

28

15

Carbohydrate analogs

Inhibition of carbohydrate processing enzymes

29

16

Carbohydrates

Inhibition of adhesion

30

17

Pilicides

Inhibition of pili formation

38

Figure 1. Development and bacterial resistance pattern of current antibiotics [9]

Figure 2. Blocking bacterial adhesion by carbohydrate anti-adhesives [33a]

Figure 3. (Top panel): Adherence of E. coli to epithelial cells in the presence of sucrose (A) and mannose (B); adapted [36] (Bottom panel): Effect of type 1 fimbriae on adherence of uropathogenic E. coli to human bladder epithelial cells in vitro (C) and inhibition of binding in the presence of methyl α-D-mannopyranoside using fluorescence microscopy (D) adapted [37]