Antibiotic, Probiotic & Lantibiotic

 

Chemotherapeutic agents are chemical substances used for the treatment of infectious diseases or diseases caused by the proliferation of malignant cells. These substances are prepared in the laboratory or obtained from microorganisms and some plants and animals. In general, naturally occurring substances are distinguished from synthetic compounds by the name antibiotics. Some antibiotics are prepared synthetically but most of them are produced commercially by biosynthesis. Microorganisms producing the largest number of useful antibiotics belong to the genera Bacillus, Penicillium, Streptomyces and Cephalosporium in addition to other chemotherapeutic agents like sulfonamides, nitrofurantoin, etc.

Criteria in choosing a useful chemotherapeutic agent:

1.     It must demonstrate selective toxicity for the disease agent.

2.     The host should not become allergic (hypersensitive) to the drug.

3.     The host should not destroy, neutralize or excrete the drug too rapidly.

4.     The organism should not readily become resistant to the drug.

5.     The drug should reach the site of infection.

SPECTRUM OF ACTIVITY
NARROW SPECTRUM	BROAD SPECTRUM
Penicillin	Chlorampenicol
Streptomycin	Chlortetracycline
Erythromycin	Demeclocycline
Lincomycin	Oxytetracycline
Polymyxin B	Tetracycline and derivatives
Colistin	Ampicillin
Vancomycin	Cephalothin
Nystatin	Gentamycin
Spectinomycin	Rifampin
	Tobramycin
	Paromomycin

MODE OF ACTION	ANTIBIOTIC	TARGET
Compete with PABA (para–aminobenzoic acid)	Sulfonamides	Enteric urinary tract infection
	PAS (para–aminosalicylic acid)	Mycobacterium tuberculosis
	Trimethoprim	Broad spectrum activity
	Compete with pyridoxine	Mycobacterium tuberculosis
Disrupt cell membrane	Polymyxins	Gram negative bacteria
	Polyene antibiotics (Nystatin, Amphotericin B)	Fungi
Inhibit cell wall peptidoglycan synthesis	Penicillin	Mostly Gram (+) bacteria
	Cephalosporin
	Bacitracin
	Vancomycin
	Ristocetin
Inhibit RNA synthesis	Rifampin	Gram (+) bacteria
Inhibit DNA synthesis	Mitomycin & Actinomycin
	Nalidixic acid	Gram (–) bacteria of UTI etiology
	Novobiocin	Gram (+) bacteria
	Griseofluvin	Fungi
Inhibit purine synthesis	Trimethoprim	Broad spectrum antibiotic
Inhibit protein synthesis	Chloramphenicol	Broad spectrum antibiotic mostly gram (+) bacteria
	Macrolide antibiotics (Erythromycin, Olendomycin Carbomycin, Spiramycin    Lincomycin, Clindamycin Tetracycline, Streptomycin)

Some organisms develop a tolerance for a new environmental condition and these organisms are referred to as drug fast or drug resistant. Drug resistance may be due to a pre–existing factor in microorganisms or it may be due to some acquired factors.

Emergence of drug resistance can be minimized by

1.  Maintaining sufficiently high levels of the drug in the tissues to inhibit both the original population and first step mutant.

2.  Simultaneously administer two drugs that do not give cross resistance, each of which delays the emergence of mutant resistant to the other drug.

3.  Avoiding exposure to a particularly valuable drug by restricting its use, especially in hospitals.

Some the of Antibiotic Resistant (ABR) Bacteria:

1.     MRSA – Methicillin–Resistant Staphylococcus aureus

2.     VRE – Vancomycin–Resistant Enterococcus

3.     CRE – Carbapenem–Resistant Enterobacteriaceae (CRE)

4.     CRAB – Carbapenem resistant Acinetobacter baumannii

5.     MDR–TB – Multi–Drug–Resistant Mycobacterium tuberculosis

Except for Mycobacterium, most of the bacteria enumerated belongs to ESKAPE bacteria group which are a group of opportunistic pathogens consisting of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species characterized by increased levels of resistance towards multiple classes of first line and last–resort antibiotic.

ESKAPE pathogens are mainly responsible for nosocomial infections and these infections are defined as hospital–acquired infections (HAIs) that affect patients within 48 hours of admission or 3 days of discharge or 30 days of an operation. No literature is available regarding the exact characteristics that classify bacteria under ESKAPE.

ESKAPE pathogens are resistant to oxazolidinones, lipopeptides, macrolides, fluoroquinolones, tetracyclines, β-lactams, β-lactam–β-lactamase inhibitor combinations, and last-line antibiotics including carbapenems, glycopeptides, and polymyxins.

The mechanisms of multidrug resistance exhibited by ESKAPE are broadly grouped into three categories namely:

1.  Drug inactivation is commonly caused by an irreversible cleavage catalyzed by an enzyme.

2.  Modification of the target site where the antibiotic may bind.

3.  Reduced accumulation of drug either due to reduced permeability or by increased efflux of the drug.

They are also able to form biofilms that physically prevent the immune response cells of host as well as antibiotics to inhibit the pathogen. Moreover, biofilms protect specialized dormant cells called persister cells that are tolerant to antibiotics which cause difficult-to-treat recalcitrant infections.

 

THE LANTIBIOTICS

Bacteriocins are antimicrobial substances produced by lactic acid bacteria (LAB), including organic acids, hydrogen peroxide, diacetyl, and inhibitory enzymes. The bacteriocin producer expresses immunity proteins to protect themselves from the bacteriocin they produce, and little was known about these proteins.

Lantibiotics are peptide-derived antimicrobial agents that are produced by the ribosomes and post–translationally modified to their biologically active forms.

Classification of Bacteriocins:

1.  Class I bacteriocins (lantibiotics) are small (<5 kDa) peptides containing the unusual amino acids lanthionine (Lan), β-methyllanthionine (MeLan) and several dehydrated amino acids. They are heat–stable and mainly induce destabilization and permeabilization of the bacterial membranes or cause pore formation into the membrane.

Examples include Nisin, Lacticin 481, and the two-component lantibiotics such as cytolysin produced by Enterococcus faecalis, lacticin 3147 produced by L. lactis, and staphylococcin C55 produced by Staphylococcus aureus.

2.  Class II bacteriocins are small thermostable peptides with an amphiphilic helical structure that allows for their insertion in the cytoplasmic membrane of the target cell, thereby promoting membrane depolarization and cell death.

a.  Subclass IIa – often designated as pediocin–like bacteriocins, constitutes the most dominant group of antimicrobial peptides produced by lactic acid bacteria. The bacteriocins that belong to this class are structurally related and kill target cells by membrane permeabilization (e.g., Pediocin PA-1, Sakacin A, and Enterocin A).

b.  Subclass IIb – the activity of these bacteriocins depends on the complementary activity of two peptides. The combined effect of the two peptides of these bacteriocins is much greater than the total activity calculated from the individual effect of these peptides (e.g., Lactococcin G, Lacticin F).

c.   Subclass IIc – also known as “Circular Bacteriocins.” They consist of the cyclic bacteriocins whose N– and C–termini are covalently linked, and the circular molecule is resistant to several proteases and peptidases (e.g., Acidocin B).

d.  Subclass IId – contains the one-peptide non-cyclic bacteriocins that show no sequence similarity to the pediocin-like bacteriocins.

3.  Class III are large (>30 kDa) heat-labile proteins that are capable of degrading cell wall murein. This group includes some colicins, zoocins, megacins (Bacillus megaterium), klebicin (Klebsiella pneumonia), helveticins I and J (Lactobacillus helveticus), and enterolysin A (Enterococcus faecalis). The new class III bacteriocin BLF3872 from LF3872 has not yet been studied.

4.  Class IV, the “complex bacteriocins” has also been suggested, which require non-proteinaceous moieties for activity. This class, however, has not been sufficiently studied at the biochemical level.

Studies on the genetics and biochemistry of bacteriocins have principally focused on members of Class I and II, due to the abundance of these peptides and their potential commercial applications.

THE PROBIOTICS

Probiotics are live microorganisms that are intended to have health benefits when consumed or applied to the body. They can be found in yogurt and other fermented foods, dietary supplements, and beauty products. The most common are bacteria that belong to groups called Lactobacillus and Bifidobacterium. Other bacteria may also be used as probiotics, and so may yeasts such as Saccharomyces boulardii.

Prebiotics are food supplements that are nondigestible by the host but can exert beneficial effects by selective stimulation of growth or activity of microorganisms that are present in the intestine.

For a potential probiotic strain to exert its beneficial effects, it is expected to exhibit certain desirable properties. The ones currently determined by in vitro tests are:

1.  Acid and bile tolerance which seems to be crucial for oral administration,

2.  Adhesion to mucosal and epithelial surfaces, an important property for successful immune modulation, competitive exclusion of pathogens, as well as prevention of pathogen adhesion and colonisation,

3.  Antimicrobial activity against pathogenic bacteria,

4.  Bile salt hydrolase activity.

There is increasing evidence in favor of the claims of beneficial effects attributed to probiotics, including improvement of intestinal health, enhancement of the immune response, reduction of serum cholesterol, and cancer prevention. These health properties are strain specific and are impacted by the various mechanisms mentioned above. While some of the health benefits are well documented others require additional studies to be established. In fact, there is substantial evidence to support probiotic use in the treatment of acute diarrheal diseases, prevention of antibiotic-associated diarrhea, and improvement of lactose metabolism, but there is insufficient evidence to recommend them for use in other clinical conditions.

Recent evidence suggests that exposure to bacteria in early life may exhibit a protective role against allergy and in this context, probiotics may provide safe alternative microbial stimulation needed for the developing immune system in infants.

Evidence also suggests that food products containing probiotic bacteria could possibly contribute to coronary heart disease prevention by reducing serum cholesterol levels as well as to blood pressure control.