Antibiotic resistance is increasing day by day over the world and this will cause a dramatic danger to the human civilization. It is now suspected that millions of people will die due to the increasing antibiotic resistance by 2050. Therefore, this increased resistance emphasizes the researchers to find new antimicrobial agents for combating microbial diseases. This article describes 15 antibiotic alternatives some of which may have strong antimicrobial effectiveness against microbial infection.
Immunomodulators provide strong effectiveness against microbial disease by inducing and enhancing an immune response. Immunomodulators include vaccines and various pharmaceutical agents among which vaccine is the most important immunomodulator.
The vaccine is the suspensions of killed microorganisms, living attenuated microorganisms or living fully virulent organisms or fractions of microorganisms that is administered to produce or artificially increase immunity to a particular disease. Vaccines include living attenuated vaccine, killed vaccine, viral subunit vaccine, nucleic acid vaccines, and Conjugated vaccine.
Living attenuated vaccine are the preparation of living but attenuated (weakened) bacteria, viruses or other agents. When administered by appropriate route to the human body, they cause subclinical or mild infection and thereby stimulates an immune response against these infections. These vaccines provide life-long immunity to the body. The example includes Sabin polio vaccine against measles, mumps, and rubella (MMR); BCG against Mycobacterium bovis.
The killed vaccine is the preparation of microbes fully killed by phenol, formaldehyde or by heat. These vaccines don’t provide life-long immunity to the body as their genome can’t be replicated because they are dead. Example; Polio vaccine, Rabies vaccine, Influenza vaccine.
Toxoid vaccines are the preparation of inactivated toxins produced by pathogens. The toxin derived from bacteria is inactivated by heat or chemical (formaldehyde) to remove toxicity without removing immunogenicity. Example; botulism, tetanus and diphtheria toxoid
Other vaccines include Viral subunit vaccine, Nucleic acid vaccines, and Conjugated vaccine.
[See More: Different types of vaccines]
- Other Immunomodulators:
Immunomodulation involves the modification of immunity to a microorganism through using cytokine or cytokine inhibitors, the modification of immunity to a specific antigen by using interferon. There are varieties of immunostimulant; but most used immunostimulant are nucleotides, thymosin, and oregano oil. Another immunostimulant such as β-1, 3/1, 6-glucan also shows health benefit by inducing an immune response against the bacterial disease.
- Phage virus
Phages therapy is now considered as the best alternative therapeutics to antibiotics because they are the viruses that cause damage to the bacterial cell. They have many advantages over antibiotics. Phage cause no harm to normal host cell because they replicate at the site of infection. Each phage is limited to a specific strain of bacteria. So they don’t harm to beneficial bacteria.
Endolysins – released from the phage virus- are the enzymes that degrade the peptidoglycan of the bacterial cell wall to allow the release of new phage from bacteria. The endolysins include glucosidase, amidase, endopeptidase, and transglycosylase that are strongly effective against various microorganisms such as Staphylococcus, Bacillus anthracis, L. monocytogenes, and Clostridium butyricum.
For example, Endolysin PAL is potential to kill Group A Streptococcus responsible for causing tonsillitis and other infections. Amidase PAL and endopeptidase Cpl-1 cause the reduction of the incidence of both local and systemic pneumococcal disease. Endolysin LysK shows good lytic activity against nine Staphylococcus, including methicillin-resistant S. aureus. Endolysin PlyV12 kills Enterococci, vancomycin-resistant E. faecalis, and E. faecium.
Comparing to the phage therapy, endolysins give more potentiality to kill susceptible strains quickly with wider antibacterial spectrum.
- Bacteriophage virion-associated peptidoglycan hydrolases (VAPGHs)
Bacteriophage virion-associated peptidoglycan hydrolase (VAPGH) is a kind of lyase enzyme that hydrolyzes bacterial peptidoglycan to facilitate the entry of phages into the bacterial cells. These enzymes are stable at high temperature retaining its antimicrobial activities.
Protein P5 from phage phi-6 exhibits lytic activity against Pseudomonas, S. typhimurium, E. coli, Proteus vulgaris, and other Gram-negative bacteria
Protein Gp181 from phage KZ shows antibacterial activity against Ralstonia solanacearum and Yersinia.
Protein gp36 of phage KMV is able to kill P. aeruginosa and E. coli.
Protein HydH5 from phage phiIPLA88, Protein 17 from phage P68 and protein gp61 from phage phiMR11 demonstrate a lytic activity against S. aureus including MRSA.
- Ribosomally synthesized AMPS
Ribosomally synthesized AMPs are synthesized in the various source of the living organisms, such as plants, insects, bacteria, mammals, amphibians etc. These AMPs have a broad spectrum anti-cellular activities as they are anti-bacterial, anti-mycotic, antiprotozoal, antiviral, and anti-neoplastic. The positive charge of these peptides is mainly responsible for the structural damage of the membranes as it binds to negatively charged phospholipid molecules on the bacterial cell membranes.
Bacteriocin is a good example of ribosomally synthesized AMPs that is produced by bacteria and active against closely related bacteria. There are many types of bacteriocins such as lacticin fermenticin, nisin, lactocin, helveticin, thuricin, sakacin, plantacin, subticin etc.
Bacteriocins show antimicrobial activities through various mechanisms of action such as; by making holes in the cell membrane, by targeting lipid II of the peptidoglycan biosynthesis machinery, by interfering with DNA, RNA, and protein metabolism.
MccB17 causes the inhibition of DNA gyrase-mediated DNA supercoiling, thereby blocking DNA replication. MccC7-C51 inhibits the function of aspartyl-tRNA synthetase, thus interfering with mRNA synthesis.
- The non-ribosomally synthesized AMPS
The non-ribosomal antimicrobial peptide (AMPs) such as gramicidin, polymyxin, bacitracin, and sugar-peptide are produced by bacteria.
Polymyxin of B. polymyxa causes an antimicrobial effect by destroying the bacterial cell membranes in many Gram-negative bacteria, such as P. aeruginosa, E. coli, Klebsiella pneumoniae, Haemophilus, and Salmonella.
Bacitracin secreted by B. subtilis and B. licheniformis, and it inhibits the synthesis of cell wall peptidoglycans and glycoprotein core oligosaccharides in Gram-positive bacteria. Bacitracin zinc and bacitracin methylene salicylic acid have been used as feed additives in USA and China since 1960 and 1990, respectively.
Probiotics are the microorganisms that cause health benefit to the host by suppressing the pathogenic microorganisms. They inhibit the growth of the pathogens by secreting various antimicrobial substances such as bacteriocins, microcins, and other organic compounds.
A lot of microorganisms are used as probiotics such as Bacillus, Lactobacillus, Lactococcus, Streptococcus, Enterococcus, Pediococcus, Bifidobacterium, Bacteroides, Pseudomonas, yeast, Aspergillus, and Trichoderma, etc.
Some of the microorganisms are used as microbiological feed additives such as B. cereus var. toyoi, B. licheniformis, B. subtilis, Enterococcus faecium, Lactobacillus acidophilus, L. casei, L. farciminis, L. plantarum, L. rhamnosus, Pediococcus acidilactici, Streptococcus infantarius, and some fungi such as Saccharomyces cerevisiae and kluyveromyces.
Prebiotics are not microbes as like as probiotics rather they are non-digestible food components. Prebiotic fibers remain undigested in the small intestine and get fermented in the large colon. This fermentation process provides nutrients for beneficial bacteria and increases the number of these bacteria. Prebiotic fiber act as fertilizer for the desirable bacteria.
The most known prebiotics are oligosaccharides, polysaccharides, natural plant extracts, protein hydrolysates, polyols, etc. The use of prebiotics as feed additives was started in the late 1990s in China.
Prebiotin selectively causes benefit to health by supporting the growth of beneficial bacteria and by inhibiting the growth of harmful bacteria.
Synbiotics is the combined preparation of probiotics and prebiotics. Simultaneous administration of probiotics and prebiotic confers dual role to the host cells. There are many beneficial reports of synbiotics in enhancing immune response, reducing diarrhea etc.
- Phytobiotics/ Plant Extracts
Plant extracts, also known as phytobiotics have been used traditionally as an antimicrobial agent for many years. There are several numbers of antimicrobial phytochemical, such as phenolics/polyphenols, terpenoids/essential oils, alkaloids, lectins/polypeptides. Most of the plant extract are secondary metabolites, such as terpenoids (mono- and sesquiterpenes, steroids, etc.), phenolics (tannins), glycosides, and alkaloids (present as alcohols, aldehydes, ketones, esters, ethers, lactones).
Phytochemicals show their antimicrobial activity by different mechanisms of action. For example, cryptolepine, causes the inhibition of topoisomerase and saponins causes damage to the cell mem9brane and consequent collapse of cells
Plant extract confers no side effect to the host cell when it is used as the antimicrobial agent.
- Quorum sensing inhibitors
Quorum sensing inhibitors (QSI) causes the inhibition of quorum sensing (QS) by blocking the QS system. There are three types of Quorum sensing inhibitors such as:
- Non-peptide QSI – AHLs (N-acyl homoserine lactones) analogs
- Peptide – AIPs (autoinducing peptide) homologs
- Protein QSI – QS quenching enzymes and QS quenching antibodies.
Furanone used in Mice causes the reduction of virulence of P. aeruginosa and apolipoprotein B (ApoB) binding with AIP1 molecules of S. aureus, effectively decreases its quorum sensing.
- Biofilm Inhibitors
Inhibition of biofilm formation is very essential to combat bacterial disease because they exhibit increased resistance to antibiotics. There are several numbers of inhibitors that decrease or prevent bacterial infection by inhibiting the formation of biofilm matrix or by dissolving it. These inhibitors, for example, oxazolidinones and tetracyclines cause the inhibition of protein synthesis, lipopeptides and glycopeptides cause the destruction of the cell membrane, and rifampin causes the inhibition of DNA and RNA synthesis to destroy staphylococcal biofilm matrix.
Fluoroquinolones in the combination with macrolides or fosfomycin reduce urinary tract infection by dissolving or inhibiting biofilm matrix.
Combination of urokinase or lumbrokinase with fleroxacin increases the destruction of P. aeruginosa biofilms by degrading the polysaccharide-protein complex in the bacterial biofilms and inhibiting bacterial DNA synthesis.
The combination of efflux pump inhibitor with miconazole can effectively eliminate Candida albicans from the biofilm matrix.
The use of enzymes as quorum sensing inhibitors enhances biofilm susceptibility by dissolving the biofilm matrix. This enzyme includes polysaccharide hydrolases, DNases, proteases and alginate lyase. Several studies show that the application of DNase and alginate lyase increases the efficacy of tobramycin against Pseudomonas aeruginosa biofilms by increasing the ability of antibiotics to penetrate the biofilm for dissolving it.
- Bacterial virulence inhibitors
Destroying virulence by inhibiting bacterial toxins may be a novel strategy to combat the bacterial disease. Anthrax toxins composed of lethal toxins (LF), edema factor (EF), protective antigens (PA) and other components. Lethal factor (LF), edema factor (EF in combination with protective antigens (PAs) causes a pathological effect. Hydroxamate and cisplatin are two bacterial virulence inhibitors that bind to the active site of this protein and inhibit the toxicities of the lethal toxins (LF), edema factor (EF), protective antigens (PA).
Cholestyramine also alleviates the toxicity of clostridial toxin thus preventing its adsorption to intestinal epithelial cells.
Acyl salicylaldehyde that inhibits the type 3 secretion system prevents the pathogenicity of Salmonella and Yersinia pseudotuberculosis.
Virstatin blocks the expression of Vibrio cholera toxin and pilus, thus inhibiting the growth of V. cholerae in the gut.
- Feed enzymes
Feed enzymes inhibit the proliferation of harmful bacteria in the gut. They do it by causing digestion and reducing the number of undigested nutrients in the large colon. Because undigested nutrients are essential for bacterial growth. The commonly used feed enzymes are the mixture of a variety of glycanases, and phytase. Many industries nowadays produce recombinant synthesized enzymes such as phytases and carbohydrases and sell it as feed additives.
Phytase plays a significant role in the digestibility of calcium, phosphorus, and minerals and causes the intestinal mucin production and the endogenous losses, supporting the growth of beneficial bacteria selectively. Xylanase is an additive of wheat-based diet which reduces the pathological effects of C. perfringens in broiler chickens.