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Monday, March 14, 2016

Got Strep Throat? Are Antibiotics a Requirement?

The aim of this review is to summarize the current knowledge of the antimicrobial activity of naturally occurring molecules isolated from plants against Streptococcus species, focusing on their mechanisms of action. This review will highlight the phytochemicals that could be used as alternatives or enhancements to current antibiotic treatments for Streptococcus species. The scope of the review is limited to inhibitory effects of phytochemicals, mainly polyphenols, against Streptococcus species and where possible, their mechanisms of action against the major virulence factors will be discussed. Due to their major implications on human health, this review has largely focused on four Streptococcus species: (i) S. mutans (ii) S. pyogenes (iii) S. agalactiae and (iv) S. pneumoniae. To explain the potential mechanisms of inhibition of the phytochemicals, S. mutans has been used as the major example.

1.4. Treatment of Streptococcal Infection
Penicillin or one of its derivatives (e.g., amoxicillin and ampicillin) are the recommended antibiotic treatment for non-allergic patients diagnosed with S. pyogenes and S. agalactiae infections [27]. For allergic individuals, azithromycin and clarithromycin are recommended and in fact, azithromycin is prescribed more commonly than penicillin [94]. For severe S. pyogenes infections like necrotizing fasciitis and toxic shock syndrome, a combination of penicillin and clindamycin are prescribed [95]. S. pyogenes and S. agalactiae are not resistant to penicillin, but over time they have become resistant to clindamycin, tetracycline, vancomycin and macrolides (e.g., erythromycin, azithromycin and clarithromycin) [27]. Clarithromycin, clindamycin and vancomycin resistance among S. pyogenes and S. agalactiae strains are most concerning [27].

1.5. Antibiotic Resistance and Emerging Threats
Antimicrobial resistance is compromising the treatment of invasive infections including severe streptococcal infections [27]. This threat becomes significant in vulnerable patients (e.g., individuals undergoing chemotherapy, dialysis and organ transplants) due to infection-related complications [27]. This puts healthcare providers in the position to use antibiotics that may be more toxic to the patient, and frequently more expensive, leading to an increased risk of long-term disability and lower survival rates [27].

According to Frieden, director of the U.S. Center for Disease Control and Prevention (CDC), antimicrobial resistance is a serious health threat in the 21st century [27]. Infections caused by resistant bacteria are now on the rise and their resistance to multiple types and classes of antibiotics is worrisome [96]. The decrease in the rate of pathogen susceptibility to antibiotics has made it much more difficult to combat the infectious diseases [27]. The CDC’s 2013 report has prioritized drug-resistant S. pneumoniae as a serious threat, and erythromycin-resistant S. pyogenes and clindamycin-resistant S. agalactiae as concerning threats [27].

1.6. Possible Alternatives for Classical Antibiotics
Plants produce diverse secondary metabolites or phytochemicals, most of which are isoprenoids and polyphenols and their oxygen-substituted derivatives such as tannins that could be raw materials for future drugs [97]. Herbs and spices contain useful medicinal compounds including antibacterial chemicals, and researchers have found that many of these compounds inhibit the growth of pathogenic bacteria [97]. Accordingly, experimental observations have shown that herbal preparations are active against many of the pathogens (Table 2).

From the period of 1981 to 2006, 109 new antibacterial drugs were approved for treatment of infectious diseases of which 69% originated from natural products, and 21% of antifungal drugs were natural derivatives or compounds mimicking natural products [98]. Various medicinal plants have recently been tested for their antimicrobial activity and all have proven that phytochemicals, particularly polyphenols, exhibit significant antibacterial activity against Streptococcus species (Table 3).

3. Conclusions and Prospects
Each class of classical antibacterial agents (antibiotics) usually targets different sites and processes of pathogenic bacteria. Major antimicrobial actions include disruption of membrane structure, inhibition of protein synthesis, and inhibition of production of folate coenzymes, nucleic acids, and peptidoglycans. Natural antimicrobials like their synthetic counterparts (antibiotics) target different molecules and processes to inhibit the colonization and viability of the bacteria or to inactivate bacterial toxins and or modulate the molecules and processes pre-requisite for bacteria’s metabolic pathways or reduce the rate of protein synthesis. It is worth noting that natural antimicrobial products not necessarily have to be bactericidal to suppress such processes and activities. It is plausible that a compound is likely to be efficient bacterial growth inhibitor if it can deteriorate the cytoplasmic pH, increase the permeability of plasma membrane, prevent extracellular and intracellular microbial enzyme production, interrupt bacterial metabolic pathways, or disrupt plaque and biofilm formation. As observed, there is considerable amount of scientific evidence that phytochemicals exert significant multiple anti-streptococcal effects and apart from their bactericidal effects, their main bacteriostatic strategy is the anti-adhesiveness attribute.

The efficacy of natural products as antimicrobials with fewer or no side effects is likely to depend on the structure of the compound that interacts with the toxin or pathogen and not with molecules of the host meaning that their effect is specific. This approach has become the rationale for natural drug design studies as a new field of research. Attempts have been made to understand certain features relating to phytochemical structure and the associated antibacterial activity. High molecular weight and complex phytochemicals exert greater inhibitory effects such as pentamer polyphenolic fraction of cocoa, high molecular weight non-dialyzable material of cranberry and F2 or F3 fractions of crowberry and bilberry. The side effects of the current antimicrobials and the spread of drug-resistant microorganisms have become a significant concern and a threat to successful therapy of microbial diseases. Therefore, there is an urgent demand for the discovery of safe natural compounds with diverse chemical structures and mechanisms of action satisfying both the consumer and the healthcare providers as potential useful therapeutic tools of the post-antibiotic era. Intensive research on such plants could lead to the incorporation of the most potent chemically defined extracts into nutraceuticals or natural health products and becoming a solution to this global concern of evolution of drug-resistant microorganisms.

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