Anti-infective Research and Development: Updates on Infection Mechanisms and Treatments E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Anti-Infective Agents
- Sprache: Englisch
This volume of Frontiers in Anti-Infective Agents provides updates on the most recent studies about anti-infective agents, their mechanism of action, the relevant molecular targets and their implication in the development of novel antibiotics that have properties similar to their corresponding compounds of natural origin. The initial chapter covers the mode of action of natural antimycobacterial compounds such as nordihydroguaiaretic acid, α-mangostin and allicin, as well as antimicrobial peptides and their role in the innate and adaptive immune response leading to the decrease of microbial resistance. This is followed by updates on tuberculosis treatment concerning the immunological role of cells (airway epithelial cells, macrophages, neutrophils and T cells) along with their products (chemokines, cytokines) and other processes such as autophagy that influence the outcome of the host immune response to the infection. Contributors have also reviewed the latest knowledge in the cellular and molecular mechanisms that trigger a protective, immune response and the identification of the molecular targets for vaccine development, all of which are a key priority to develop control measures against Babesia species like Babesia bovis and Babesia bigemina. Additionally, the neuro-endocrine and neuro-immune mechanisms behind host responses against stress and environmental stimuli during infections are also covered in separate chapters. The volume also provides updates related to Helicobacter pylori pathogenesis. The reviews presented in Anti-infective Research and Development provide timely updates for scholars and professionals associated with the field of antimicrobial research and development.
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Veröffentlichungsjahr: 2020
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PREFACE
A plethora of anti-infective agents is found in nature. Their properties and the mechanism of action are also diverse for treatment and vaccination against intracellular microorganisms (J.M. Favela-Hernandez and G.G. Guerrero). In the last decades, there was an increase in the emergence and reemergence of multi-drug resistant strains. Unfortunately, despite intense efforts, for most of these infectious diseases, there are no safe and effective treatments that are affordable for people in developed countries. Moreover, the pathogens have developed a successful evasion mechanism to survive the host selection pressure at the molecular and neuro-immunological level (A. Montoya Rosales and Noe Macias-Segura). In recent years, it has become evident that there is a connection between the nervous, endocrine and immunologic system that play a key role in the homeostatic control in the presence of different environment stimuli and infectious diseases caused by a virus, bacteria, fungus, and parasites (A. Montoya Rosales and Noe Macias-Segura). For this reason, it is pivotal to continue the search for novel and effective natural products showing an action against tuberculosis to decrease the incidence and prevalence of this pathogen (S. Guzman Beltran, F. Hernandez-Sanchez, and M.O. Barrientos). The innate and cellular immune response to M. tuberculosis infection is characterized, addressing specifically the innate components in the up-respiratory tract (URT), cytokines, antimicrobial peptides’ induction and activation of T cellular responses to promote the clearance of the M. tuberculosis (M.A. Moncada and M.A. Herrera-Barrios). Interestingly the induction of the antimicrobial peptides (AMPs) such as Cathelicidins (LL-37) and β-defensins (HBD-2), represents one of the most promising approach, along with the reactive oxygen species (ROS), to kill intracellular bacteria. Furthermore, the induction of AMPs in response to bacterial stimuli can be enhanced by vitamin D and IFN-γ in several infections (E.L. Carreto-Binaghi and Y. Gonzalez). The deleterious effect of the reactive oxygen species (ROS) can be ameliorated by vitamin D, which at the same time, can regulate nitric oxide (NO), leading to cell integrity protection and an antimicrobial mechanism by the induction of AMPS and autophagy. As a lysosome-based degradation pathway and recycling mechanism of cellular components, autophagy has been proposed as an immunological response to circumvent the escape of bacteria. If this can be approached therapeutically with autophagy inducers (natural products, drugs), is an issue that deserves further clinical consideration (A. Ruiz and E. Juarez).
On the other hand, gastric and peptic ulcers caused by Helicobacter pylori represent a serious health problem due to the increasing evidence that suggests that this gram-negative spiral bacteria predispose to gastric cancer and anemia. The enormous iron requirements of this bacteria can be fulfilled by different human sources. How can this be accomplished? And how this allows the bacteria to survive? Are the subjects of intense research for the clinic and therapeutic implications (T.J. Olivares and J. Mosqueda).
Finally, genomic studies have allowed a step forward in the identification of new genes as candidates vaccines with therapeutic potential against parasites such Apicomplexa protozoan, e.g. Babesia bigemina) of animal organisms, including humans. The understanding and elucidation of the cellular and molecular mechanisms that trigger a protective, immune response, play a key role in eliminating this type of pathogen and, thereby, are fundamental for clinical translation (J. Mosqueda, S. Mejia-Lopez. and U.M.A. Mercado).
In the present book, we aimed to update key aspects of the development and research of anti-infective agents in terms of how they can influence the host response at the pharmacological and immunological level against microbial and parasites infections. Thus, I hope this book can be helpful for readers of different disciplines to get updates on these main aspects.
List of Contributors
The Anti-Infective Agents
Juan Manuel Favela-Hernández1,Gloria G. Guerrero Manriquez2,*Abstract
Anti-infective agents are secondary metabolites produced and obtained from a different sources (plants, bacteria, virus, fungi, and marine oceans) with antibacterial or antiviral properties. The mechanism of action of these compounds is also broad and extensive as well. Anti-infective agents (antibacterial or antiviral) possess either a bactericidal/virucidal or bacteriostatic /virustatic ability against microbes and viruses. To impact as safer alternatives for the treatment of emergent and reemergent infectious diseases, it is neccesary to have a better knowledge of the more recent advances in phytomedicine, etnopharmacology, and omics technologies that might lead to therapies a based on natural formulations of adjuvants and/or of different combinations of compounds (e.g. secondary metabolites+antimicrobial peptides) with complementary properties (immunological, pharmacological), that are a promised strategy to curb multidrug resistance strains (MDR) and/or super drug resistance bacteria (XDR). Therefore, the aim of the present chapter is to outline the world of anti- infective agents, along with their mechanism of action.
INTRODUCTION
The emergent and reemergent resurgence of old infectious diseases (measles, tuberculosis, leprosy) represents a threat to human beings in developed countries [1]. First second and third-generation antibiotics have been the alternative as a treatment against infectious diseases. However, the recent uprising of Multi-drug resistant (MDR), and Extensively-drug resistant (XDR) such as Super Bug resistant (SBR) strains of Staphylococcus aureus. (S. aureus) has curbed the functions of antibiotics used for the treatment of infectious diseases (bacterial/viral) nowadays (Fig. 1).
To overcome the MDR, it has been proposed to use a combination or a mixture of
different compounds with different properties that can be given as additives to make a synergy that potentiates the pharmacological as well as the immunological effects (e.g. drugs and antimicrobial peptides). More recent work has suggested virustatic agents that can be repurposed to virucidal agents using high throughput technologies [2-9].
In the present chapter, we revisited the anti-infective agents from natural sources by highlighting their mechanism of action and at the same time, we outlined the mechanisms of resistance. We think that host-pathogen interaction analysis in conjunction with the more recent advances in phytomedicine, ethnopharmacology, and omics technologies may lead to a better understanding and development of natural effective therapies as well as innovative technologies in clinical immuno-pharrmacology research.
SOURCE OF THE ANTI-INFECTIVE AGENTS
A plethora of anti-infective agents (either antimicrobial and/or anti-viral) are secondary metabolites, isolated and extracted from different natural sources (plants, bacteria, fungi, virus and marine oceans) [10-13] but they can also be chemically synthesized. The mechanism of action of anti-infective agents in general can be direct and irreversible (bactericidal/virucidal) or indirect and reversible (bacteriostatic/virustatic) depending on the intrinsic properties of the anti-infective agent [14-18].
The bactericidal agents can exert their action toward Gram(+)[Staphylococcus aureus, Streptococcus pneumonia, Clostridium perfrrngerns, Clostridium tetanic; Listeria monocytogenes, Mycobacterium tuberculosis]. Whereas the bacteriostatic agents can act against to Gram (-) bacterias, (Pseudomonas aeruginosa, Campylobacter jejuni, Salmonella tiphi, Vibrio cholera, Escherichia coli, Helicobacter pylori, Haemophilus influenza) and DNA viruses (Parvovirus, Papovavirus, Adenovirus, Iridovirus, Poxvirus, Herpes, Hepadnaviruses) or RNA viruses (Rabdovirus, Togavirus, Bunyavirus, Coronavirus, Arenavirus, Retrovirus, Paramyxovirus), see viruses section [14-18].
Fig. (1)) A-Scheme of the main human infectious diseases caused by gram postive (+) and gram negative (-) bacteria. Some of them are shared eihter by both types of bacteria. Some of them are still a serious health problema worldwide due to appearnce of multidrug resistance strains (MDR) and/or super drug resistance bacteria (XDR). (e.g. Staphylococcus aureus,Salmonella typhimurium; Mycobacteirum tuberculosis). Other infectious diseases like those caused by Helyobacter pylori constitute a major risk for cáncer development. Bacterial toxins produced by the genus Clostridium, Bacillus, Vibrio cholerae, E. coli enteropathogenic, comprise a powerful virulence factor in the interaction host-pathogen) and potential target; quórum sensing and biofiilm foramtion by P aeruginosa as well.Plant-Derived Anti-bacterial Agents
Plant-derived secondary metabolites possess a variety of biological properties. Pharmacological or toxicological and recent studies indicate that glucosides triterpenes are potential adjuvants in cáncer and other inflammatory diseases [19-22]. Phenols and phenolic acids ((PCs) (flavonoids and nonflavonoids), tannins, anthocyanins, stilbenes, coumarins, tannins, lignans and lignins) are one of the most potential antimicrobial agents derived from diverse natural sources such as from fruits, vegetables, seeds, vegetables, tea, wine and honey. Around 400 products have been described with these properties [23, 24], whose chemical structure can neutralize reactive species of oxygen (ROS) (anti-oxidant activity) and can interact positively with gut microbiota. The hydroxyl group in the molecules of the PCs has been associated with the inhibitory effect exerted by PC on target bacteria.
The fruit rich in PCs (taxifolin, myricetin and quercetin) is blueberry, active against L. monocytogenes and Salmonella enteritidis [23, 24]. In addition, PCs such as as caffeic acid have antibacterial activities to Escherichia. coli (E. coli) and Staphylococcus aureus (S. aureus). Whereas, gallic acid is active against Enterococcus faecalis (E. faecalis) and also against Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Moraxella catarrhalis (M. catarrhalis) Streptococcus agalactiae (S. agalactiae) and Streptococcus pneumonia (S. pneumoniae), Campylobacter jejuni (C. jejuni) and Helicobacter pylori (H. pylori). Moreover, gallic acid has also shown bactericidal activity and immunomodulatory properties against Campylobacter coli (C. coli) and Listeria monocytogenes (L. monocytogenes) [25]. Besides, phenolic compounds (PC) as drug candidates for Tuberculosis therapy have also been effective [26].
Potentilla species were found to be rich in hyperoxide, (+) catechin, caffeic acid, ferulic acid, rutin, and ellagic acid, which were tested for their antibacterial activities. Potentilla fruticosa has the highest effect against S. aureus, S pneumonia (Gram-positive bacteria); P aeruginosa, P. mirabils (Gram-negative bacteria) (Fig. 1) and/or toward the fungus Candida albicans.(C. albicans) [27]. Other phenolic compounds such as hydroquinone, thymol, carvacrol, butylated hydroxyanisole and octyl gallate were assayed against S. aureus [28].
Panduratin A, a natural chalcone compound, extracted from Kaempferia pandurata ROxb, had potent activity against S. aureus [27]. Zheng et al., 2014 [29] reported around 100 natural products with inhibitory activities against Mycobacterium tuberculosis (M.tuberculosis, MTb) proteasome [29]. Among them, 22 are phenolic compounds; flavonoids, coumarins, phenol and lignans. These include baicalein, pectrolinari, quercetin, hispidulin, myricetin, Isoliquiritigenin icariin, kaempferol, curcumin, and baicalin. The main target of phenolic compounds, particularly lignans (dihydrocubebin, hinokinin, ethoxycubebin) are the biosynthesis of mycolic acids of M. tuberculosis (Gram-positive mycobacteria) (Fig. 1) [29, 30].
Triterpenes, the sesquiterpenoids, whcih are a class of terpenoids composed of three isoprenes units (15 carbons), as antiinfective agents, have antioxidative and anti-inflammatory properties and can function as neuropeptides A clear example is Quillaga saponaria or QS-21 [27] which has been shown to be promising in some assays as a vaccine in terms of efficacy and toxicity [27]. Riccardi, a natural product of liverwort and 6,6’dihydrothiobinupharidine (from the crude drug Senkotsu [31] can also be found in volatile oils obtained from different parts of plants like flowers, leaves, seeds, stems, roots and wood [32, 33]. They are characterized by a strong smell and by variable mixtures of bioactive compounds mainly terpenoids (monoterpenes and sesquiterpenes). Some of them also contain nonterpenic compounds by the phenylpropanoid pathway., e.g. Eugenol, Cinnamaldehyde and Safrole [34]. These compounds exhibit antibacterial properties against Gram-positive bacteria (S. aureus) and Gram-negative bacteria (Salmonella enteritidis, Pseudomonas aeruginosa, Yersinia enterocolitica) [34].
Alkaloids represent another type of natural products isolated from plants, animals, bacteria and fungi. They are considered as healing secondary metabolites. In general, most of the alkaloids are bactericidal rather than bacteriostatic. Thus, for example, Squalamine showed higher bactericidal activity than bacteriostatic [35]. Other alkaloids with antimicrobial, antiviral and anticancer activities are the dehydrocavidine, coptivine, dehydrospocavidine and tetrahydroscoulerine of Yanhuanglian extracted from Corydalis Saxicola Butning [35].
Plant-Derived Antiviral Agents
Around 40 compounds of this type have been observed that possess antiviral activity (virucidal). Leurocristine, periformyline, perivine and vincaleucoblastine are natural alkaloids that have been obtained from Catharanthus roseus (L) and lanceusPih (Apycycaceae). Leurocristine is active against poliovirus, vaccinia, and influenza viruses [36]. Periformyline inhibits poliovirus replication [36]. Perivine exhibits activity against vaccinia, and vinaleucoblastine possesses virucidal activity against poliovirus vaccinia and influenza virus [36]. The michellamines naphthylisoquinoline alkaloids obtained from the tropical liana Ancistrodalus korupensis have demonstrated HIV-inhibitory activities [37]. A series of isoquinoline alkaloids such as lycorine, lycoridicine, narcidasine, and cis.dihydronarciclasine, obtained from Narcissu poeticus (Amaryllidaceae) have shown significant in vitro activity against flaviviruses and bunyaviruses (Fig. 2) [38, 39].
Fig. (2)) The antiinfective agents are compounds that are obtained from different sources, In general are derived from either, the nature (plants, bacteria, fungi, marine oceans, animals) or chemically synthesized. The most common plant derived compounds are the alkaloids (chalcone), phenolic acid (flavaonoids, terpenoids), which exert their activity directly (bactericidal) or indirectly (bacteriostatic) leading to a loss of cellular integrity or disruption of any processes (cell growth, cell viability, protein biosynthesis, DNA replication) or structure (membrane integrity). In a similar concepts is applied for viruses.OTHER SOURCES OF ANTI-INFECTIVE AGENTS
The bacterium Chromobacterium violaceum, is a Gram-negative bacteria that produce violacein considered as a bioactive metabolite involved in quórum sensing. This is one of the thousands of possibilities that can be explored from pathogens and the unveiled interaction between host-pathogen components [40]. Another bacteria that produce beta-lactamase (inhibitor of cell wall biosynthesis) belong to the Streptomyces genus [41]. By other hand, wild polish mushrooms, containing protocatechuic acid, 4-hydroxybenzoic acid, vanillic acid, syringic acid, caffeic acids, p-coumaric and ferulic acids, show antibacterial activities against a range of Gram (-) and Gram (+) bacteria [42] while the effect is stronger against Gram(+) microorganisms. Methyl gallate is effective against enterobacteria such as S. typhi, E. coli and S. flexneri [42]. Interestingly, marine-derived anti-infective agents have also been described particularly with their antimycobacterial activity [43, 44].
MECHANISM OF ACTION OF THE ANTI-INFECTIVE AGENTS (BACTERIAL/VIRAL)
In general, the anti-infective agents (antibiotics natural and synthetic, secondary metabolites) target key áreas in the bacterial life such as protein synthesis, folate pathway, DNA replication, cell wall biosynthesis, and also structures such as the external membrane. Of note is the action of the antiviral compound whose main action is viral binding, viral replication and blockade of the DNA enzymes (Fig. 3).
Fig. (3)) The cell envelope of Gram positive and Gram negative bacteria is a complex barrier characterized by a thick layer of peptidoglycan (PG) immersed in the periplasmic space and connected to the internal cytoplasmic membrane. In Gram negative bacteria, is comprised by two membranes, an intersticial or the periplasmic space in which is inmersed a thin layer of peptidoglycan (PG). The cell Wall polymeric structure is comprised by glycan strands covalently linked to each other (in a perpendicular fashion with respect to the length of the glycan strands) by an interconnecting peptide stalk attached to an alternating saccharide of the glycan strands.. In Gram negative bacteria, the full length stalk structure is the peptapeptide L-Ala-γ-D-Glu-meso-diaminopimelate-D-Ala.D-Ala(lysine replaces the diaminopimelate in many Gram positive cell walls. The chemical composition in either cell envelope of Gram positive and Gram negative is based on membrane binding proteins (BNPs), polysaccharides polymers, phospholipids, and teichoic acids.Bactericidal Anti-infective Agents
A bactericidal anti-infective agent is a compound that can damage and disrupte the external membrane or the cell wall biosynthesis, causes an irreversible change, affecting bacterial viability and a leaky memabrane either from Gram positive or Gram negative bacteria as outlined in Fig. (2) [45-50], e.g. Ethambutanol [51]; Ethionamide [52-54]; and Cephalosporins [55, 56] are able to block Gram-positive cell wall biosynthesis (Fig. 3).
-Ethambutanol (EMB) (a first-line antibiotic for Tb treatment), has a cell wall acting as an antibiotic that targets enzymes that are part of the mycolic acid synthesis machinery [51], thus limiting the apical growth (mycolic acid synthesis) and inhibiting arabinogalactan, a component of the cellular membrane of M. tuberculosis [27].
-EMB remains as the most effective against mycobacteria, which requires an mAGP layer for viability. Furthermore, EMB is also the drug of choice for treating various infections caused by non-tuberculous mycobacteria (NTM) [51]. To note EMB also has an effect on Corynebacterium glutamicum (C. glutanicum) growth [50].
-Ethionamide and prothionamide are prodrugs that are activated by EThA and inhibit the synthesis of mycolic acid [49-51], whereas cycloserine antibiotics also inhibit the peptidoglycan synthesis, another major component of M. tuberculosis cellular membrane [52-54].
-Ceftazidime and apigenin damage the cytoplasmic membrane of ceftazidime-resistant Enterobacter cloacae and cause subsequent leakage of intracellular components and inhibition of bacterial energy metabolism [55, 56].
-Isoniazid is a prodrug that is activated by the Mtb catalase-peroxidase (KatG) and inhibits the synthesis of M. tuberculosis mycolic acid [57, 58].
Bactericidal Plant Derived- Secondary Metabolites
Phenolic compounds (flavonoids, non-flavonids, triterpenes, butyric actidcin-namic acid and thymol) can damage and irreversibly alter bacterial cell membrane accompanied by changes in permeability, polarization as well as the interruption of flux activtiy. Polyphenols constitute a promising weapon against nosocomial infections if S aureus strains are present [59-62]. Tannins, which is one of the most representative phenolic compounds [subclassified into condensed tannins (proanthocyanidins orcatechins) and hydrolyzable tannins (gallotannins and ellagitannins) [59-61] are able to penétrate and interact with lipid bilayers and can cause a membrane fusion, a process that results in the leakage of intramembranous materials and aggregation [59-61]. Triterpenes like Quillaja Saponaria or QS induce a membrane leakage and 6,6’dihydrothiobiparidine-inhibited DNA topoisomerase IV exerts a synergistic effect either with drugs against multiresistant strains of S. aureus (MRSA) or with vancomycin against resistant bacteria of the genus Streptococcus [63, 64]. Squalamine (s polyamine alkaloid class) acts by disturbing the bacterial membrane integrity [65]. Sanguinarine (a benzo phenanthridine alkaloid) obtained from the root of S. canadensis I., acts through the release of autolytic enzymes, and destroys tissues when applied to the skin (Fig. 3) [66].
Antimicrobial peptides are one of the best examples of this type of anti-bacterial agent is the cationic peptides (AMPs), a stretch of +2 - 11 aminoacids and even more +34 aminoacids (a.a.) are promising and potential antibiotics that can interfere with microorganism virulence [67-69]. Cationic peptides can easily cause a leaky membrane due to their amphipathic nature and secondary structure. AMPs are considered one of the most promising antiinfective agents able to trigger host innate immune response [70-72]. Examples can be listed, colistin, melittin, indolicidin, risin, CAMA, defensins, protegrins, magainins, etc [67-69], which have been reported as bactericidal or haemolytic molecules (Fig. 3) [73, 74].
Bacteriostatic Anti-Infective Agents
They are capable of inhibiting or limiting bacterial growth by blocking protein biosynthesis, DNA i.e., drugs, extracted from natural sources or chemically synthesized, perform in a bacteriostatic mode of action against some variant colonies of S. aureus. e.g., daunorubicin, ketoconazole, rifapentine and sitafloxacin [49, 50].
Drugs
Tetracycline derivatives, as well as sulphonamides, are bacteriostatic drugs. Tetracyclines have a high affinity to form chelates with polyvalent metallic cations such as iron (Fe3+, Fe2+), aluminum (Al3+), magnesium (Mg2+) and calcium (Ca2+) [75], while sulphonamides inhibit folic acid metabolism pathway [76]. 4-aminosalicylic acid (PAS) (a second-line anti-TB drug) was initially used as a first-line anti-TB drug before the discovery of rifampicin and pyrazinamide. Although the mode of action of PAS is unclear, it is thought to act by inhibiting dihydrofolate reductase (DHFR) in the folate pathway of M. tuberculosis [77].
Aminoglycosides such as kanamycin and amikacin and the cyclic peptide, Capreomycin, act by protein synthesis inhibition [78]. Fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin show anti-TB activity through the inhibition of DNA gyrase [79, 80]. Rifampin acts by inhibiting RNA synthesis through binding to the DNA-dependent RNA polymerase of M. tuberculosis [81]. Pyrazinamide is a prodrug that is activated in its acidic form by pyrazinamide of M. tb and inhibits mycobacterial growth [82].
Bacteriostatic Activity of Bacteria-derived Secondary Metabolites
Piericidin A and Glucopiericidin A are two potential inhibitors of the quórum sensing (QS) system produced by the Streptomyces Xanthocidicus (S. xanthocidicus) KPP01532 strain against plant pathogens (and applied for the control of potato soft rot caused by erwinia carotovora subsp. atroseptica [83].
Bacteriostatic Activity of Plant-derived Secondary Metabolites
Secondary metabolites that are plant-derived act by the inhibition of biofilms [84]; a different system of M. tuberculosis such as [85-87] the inhibition of virus replication, inhibition of viruses binding, and inhibition of DNA enzymes (Fig. 2) [88, 89].
Phenols can act through interaction with sulfhydryl groups in microbial enzymes, leading to inhibition of those enzymes through non-specific protein interactions. Phenolic compounds (flavonoids, nonflavonoids, triterpenes, butyric actid cinnamic acid and thymol) are able to inhibit virulence factors such as enzymes and toxins and suppress the bacterial biofilm formation (Fig. 2) [90].
Flavonoids are able to form a complex with cell wall components and consequently inhibit further adhesions and, therefore, limiting microbial growth. Flavan-3-ol, isofalvons and flavanoid compounds inhibit nucleic acid synthesis through the inhibition of topoisomerases and dihydrofolate reductases and alter cytoplasmic membrane function, (posibly by generating hydrogen peroxide) (Fig. 3) [91]. Furthermore, flavonoids with antimycobacterial activity have the ability to inhibit proteasome inhibition and mycolic acid biosynthesis [85-87]. Other secondary metabolites with antimycobacterial activity are plant-derived from Byttneria herbacea, which have also exhibited a potential activity of inhibition of glutamine synthetase and have activity either in growing and/or dormant Mycobacterium. In a similar way, the herbal composition PHY906 consisting of Scutellaria baicalensis, Ziziphus jujuba, Glycyrrhiza uralensis and Paeonia lactifloa and extracts of aerial portions of Leucas stelligera contains di-terpenes and flavones that have antimycobacterial activity [85-87].
Phenolic rich fruit extracts or individual fruit-related PCs act against bacterial cells. Modifications occurring in the regulation of genes associated with certain virulence features in the microorganism include hydrophobicity, adhesión, motility, invasión, and inhibition of porins (integral membrane proteins) [92-94]. Phenolic acids like gallic, vanillic, syringic, p-coumaric, ellagic and protocatechuic acid are able to make changes in the fatty acid membrane composition to different ranges of concentration and thus, have the capacity to dampen bacterial spread dissemination of S. aureus, E. coli [16, 24-26]. Epigallocatechin gallate (EGCg) limits bacterial growth and invasión observed at suboptimal doses against species of Staphylococcus by the inhibition of the Tet(K) efflux pump. In addition, gallic acid is well known for antimicrobial and immunomodulating properties [94, 95].
Alkaloids are most of the secondary metabolites derived from alkaloids are able to inhibit the bacterial enzyme dihydrofolate reductase, thereby inhibiting nucleic acid synthesis [96, 97]. The alkaloid quinolones, is also able to inhibit key enzymes in the bacterial metabolism, while the alkaloid Agelasines, inhibits dioxygenase enzyme BCG 3185c, causing a disturbance in the bacterial homeostasis [98].
Volatile oils (EOS) obtained from different parts of a plant have the ability to interfere in bacterial physiological and biochemical processes during their development and multiplication. Cinnamon oil is amongst the most effective EOSs against foodborne pathogens. The effect of these EOSs depends on either Gram (+) (S. aureus, S. pneumniae, M. tuberculosis, L. monocytogenes, C. diphteriae, C. perfringes) or Gram (-) (B. melintensis, B. aboruts, P. aeruginosa, N. gonorrhea, H. influenzae, H. pylori, V. cholerae, S. typhi, E. coli enteropathogenic) (Fig. 1), since the lipopolysaccharide (LPS) layer in gram-negative bacteria acts as a barrier for macromolecules and hydrophobic compounds such as those present in volatile oils (EOs) (Fig. 3) [99].
Interestingly, these compounds have shown immunomodulatory effects of EO on the secretion of important cytokines in stimulated cell culture with LPS as well as in the inflammatory pathways such as nuclear factor-kappa light-chain-enhancer of activated B cells (NF-kB). At low concentrations, EOs can induce cytotoxic effects [99].
MECHANISM OF BACTERIAL RESISTANCE
Modification of protein targets of antibiotics.Production of enzymes which can degrade or modify the antibiotic structure rendering unsuccessful and ineffective treatment.The use of pumping systems to expel antibiotic molecules.Modification of Protein Targets of Antibiotics
Resistance-modificative agents (RMAs) such as polyphenols and phenolic acids as well as other anti-infective agents, can be more plausible to develop using in silico EBSCO bioinformatic studies. Phenolic compounds can diminish antibiotic resistance of S. aureus clinical strains [101, 102]. The green tea (Camellia sinensis) rich in catechins has the capacity to reverse methicillin resistance in MRSA isolates at lower concentrations than those needed for the inhibition of bacterial growth [102]. Catechin has a modulatory effect on bacterial drug resistance. One mechanism of resistance that some charged molecules like antibiotics develop is the interaction on the cell surface, which reduces or decreases the interaction of cationic peptides with the bacterium. Among other mechanisms that lead to resistance to AMPs could be the decrease in the permeability toward the cells, secretion of proteases reléase of AMP degrading enzymes, downregulation of host responses, active efflux, and alteration of membrane physiology [103].
Production of Enzymes which can Degrade or Modify the Antibiotic Structure
MTb proteosome plays a crucial role in providing intrinsic resistance against deleterious effects of reactive nitrogen intermediate (RNI) such as nitric oxide (NO) and radical NO2 that are produced by the inducible nitric oxide synthase (iNOs) in activated macrophages, all of which inflict nitrosative stress to MTb. NO may also combine with superoxide from bacterial metabolism to form peroxynitrite that inflicts oxydative damage to MTB [103, 104].
The intrinsic resistance can be attributed to cell wall permeability and system efflux pumps that mediate only selected solutes, be it hydrophilic or hydrophobic to enter into the bacteria and extracting foreign compounds out from the bacteria. Mutations in the chromosome in the gene encoding drugs target drug activating enzymes. This results in the alteration of the structure of the target proteins, hence reducing the susceptibility of the bacteria to a particular drug [105, 106].
The Use of the Pumping Systems to Expel Antibiotic Molecules
Regulatory genes controlling multidrug resistance by the expression of efflux pump and bacterial biofilm formation also show important roles in antibacterial resistance. Nowadays, several diverse strategies are being designed and employed against MDR. Among them, the new generation of antibiotics, combination therapy via natural antibacterial substances and also use of drug delivery systems represent important advances in the field [105].
HOW ENVIRONMENTAL STRESS IN BIOFILMS CONTRIBUTES TO THE BACTERIAL RESISTANCE MECHANISM
Biofilms formation by a microorganism is like a matrix composed of polysaccharides, proteins and extracellular released nucleic acids. One of the main functions of the bacterial biofilms is that they decrease the penetration of antimicrobial agents [100, 105]. S. auresu and Staphylococci and/or S. mutants can capture positively charged molecules through the extracellular polymeric biofilm matrix, but it can also concéntrate the bacterial enzymes which inactivate antibiotics. Biofilm formation can be viewed as a bacterial resistance mechanism and defense against several environmental stresses that can limit bacterial survival. Gradients of nutrients, metabolites, oxygen, pH, redox potential or antibiotics can penétrate the biofilm and cause the expression of an inducible resistance mechanism, increased mutability rate and bacterial adaptive phenotype changes [106]. These changes lead to metabolic suppression of bacteria, which causes increased ability to survive the exposure to antibiotics and an increasing rate of persistence cell formation. The epigallocatechin gallate (EGCg) inhibition of S. aureus biofilm formation at subinhibitory concentrations, has been shown to decrease slime layer production [106, 107].
HOW NATURE APPROACHES THE MICROBIAL RESISTANCE
The paucity of infections in wild plants supports the role of the innate defense system in plants. Most of the researchers focus on how the anti-infective agents (either anti-bacterial or antiviral) can target mainly bacterial resistance mechanism. A promising alternative versus antibiotics that has been proposed to able to overcome bacterial resistance mechanism, is the secondary metabolites derived from natural extracts. In addition, a therapy based on the combination of plant extracts, antibiotics and antimicrobial peptides can also be considered a suitable option [106-108]. Furthermore, phenols and phenolic acids could serve as good and potential candidates as natural anti-bacterial arsenals as well as good adjuvants of antibiotics. A clear example is the combination of:
(a) Phenols compounds such as catechols or resorcinols and pyrogallol, which showed a higher potent activity rather than individual compounds [2, 29] against a number of microbial complexes as causal agents of periodontitis. One complex (so-called “red complex”) is comprised of Gram-negative bacteria (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) [109, 110]. The second complex consists of Gram-positive bacteria (Peptostreptococcus micros. Eubacterium nodatu and Streptococcus constellatus) [111, 112] as well as Gram-negative bacteria (Campylobacter rectus, Campylobacter showae, and Campylobacter gracilis). A third complex formed mostly of Gram positive bacteria S. sanguis, S. oralis, S. mitis, S. gordonii and S. intermedius (Figs. 1 and 2) [112-114]. A fourth complex comprised of Gram-negative bacteria such as Campylobacter concisus, Eikenella corrodens and Actinobacillus actinomycetemcomitans serotype a [115-117] and a fifth complex consisted of Veillonella parvula and Actinomyces odontolyticus (Actinomuces odontolycus); Aggregatibacter. Actinomycetemcomitans serotype b, Selenomonas noxia and Actinomyces naeslundii genospecies 2 (Actinomuces viscosus) (Figs. 1 and 2) [116-118].
(b) Pyrogallol-based compounds are more potent than others such as catechol or resorcinol, gallic acid and hydroxycinnamic acid (ferolic acid) to destroy bacterial cell wall of S. aureus (Gram positive bacteria); E. coli and P. aeruginosa (Gram negative bacteria) leading to leakage of cellular contents. These compounds have exerted strong activity against Gram (+) microorganisms (Figs. 1 and 3) and some of them showed good synergism with antibiotics.
(c) Pentagalloylglucopyranose, combined with penicillin G, was active against methicillin-resistant S. aureus.
(d) The combination of epicatechin gallate and oxacillin reduced around 500 times the minimal inhibitory concentration by the addition of epicatechin gallate to the antibiotic (Figs. 1 and 3) [119].
Antibiotics synergy is also an important strategy to control drug resistance by targeting more than one site of action which increases the bioavailability and/or modify the resistance mechanism induction [69, 89]. In the study on multidrug-resistant bacteria, antimicrobial peptides (colistin, melittin, indolicidin, risin, CAMA, defensins, protegrins, magainins, etc) with bactericidal activity that work throughout detergent-like mechanisms against P. aeruginosa [37, 82, 120-123], constitute one of the most promising alternatives against MDR bacteria. Another property that indolicidin (isolated from bovine neutrophils) possesses is the haemolytic activity. How the AMPs avoid the resistance developed by microbials is that its action is so fast that the bacteria do not get the chance to mutate or express resistance genes and/or prepare their defense [40-45, 103, 112].
CONCLUDING REMARKS
Plant-derived metabolites or compounds with antibacterial activity (leaves or roots) form healthy specimens; however, there is evidence that key components of plant defenses against phytopathogens are induced by infection. Plants respond to microbial attack through a highly coordinated repertoire of molecular, cellular and tissue-based defensive barriers to colonization and invasión. PCs that are fruit-derived can be explored for innovative therapies against pathogenic microorganisms in human, veterinary medicine, and agro-food industry. For the design and development of innovative therapies for medical use, anti-infective agents should be able to modulate some important virulence factors of bacteria, such as adhesivity, biofilm formation and the phenomenon of bacterial persistence.
As highlighted from medicine advances, antibiotics are considered one of the most important contributions against infectious diseases. The challenge of the natural products derived from diverse natural sources lies in the translation of research from in vitro to in vivo studies, and hence to human clinical trials that will lead to the development of new phytochemicals. Different programs have been proposed as alternatives or strategies to face multidrug-resistant viruses and bacteria (WHO). The first thing is the use of antimicrobial peptides that have a bactericidal action and a role as an immunomodulator of the innate host response. The use of natural products (secondary metabolites) in conjunction with antibiotics in an appropriate dose and route of administration and different targets might be a weapon to tackle microbial resistance mechanisms. Therefore, the knowledge and understanding of the mode of action of pathogens (bacterial or viral) concurrent with the advances in innovative technologies might allow the development of more effective and safe treatments in developed countries.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors confirm that the content of this chapter have no conflict of interest.
ACKNOWLEDGEMENTS.
The authors are grateful for the financial support of SEP (PERFIL PRODEP 2019-2022 - GGGM) and CONACYT (FHM and GGGM).
