Marine Environment: A Potential Pool of Isolating Antibiotic Producing Bacteria with Novel Characteristics

Aims: This review article analyze the data based on antibiotic producing bacteria isolated from different poles of marine environment globally and further more their antibiotic potential against different pathogenic microbes. Microorganisms are potential source of metabolites with useful antimicrobial, antiviral and anticancer properties. Especially microbes of different environment show versatility in antibiotic producing ability. Thus there is always a


INTRODUCTION
An agent that inhibits bacterial growth or kills bacteria and other microorganism is called antibiotic. Antibiotic is a substance that is produced by a microorganism that is antagonize the growth of other microorganisms in high intensity [1]. It is essential to control the growth of unwanted microorganisms in every aspect of life that causes infectious diseases in plants, animals and humans [2,3]. The basic difference between antibiotics and chemotherapeutic drugs is that antibiotics are synthesized by numerous bacteria and fungi so these are natural drugs, while chemotherapeutic are synthesized by man, so these are categorized under synthetic drugs [4]. Although chemotherapeutic drugs are good but in medical implication the multiplicity of microorganisms and their secondary metabolites is supreme and matchless [5]. In modern pharmaceutical industry some of the most important products have been yielded from microorganisms because they are a productive source of structurally diverse bioactive metabolites [6]. This article focuses on the potential role of antibiotics producing bacteria isolated from marine environment of different countries against different human pathogens.

HISTORY OF ANTIBIOTICS
History of antibiotics began in 1928 when a British scientist Alexander Fleming observed that bacterial growth can be inhibited by another organism. He observed that a mold, which contaminated the Petri plate he was working on, inhibited the growth of bacterium Staphylococcus aureus. The mold was Penicillin notatum and the antibiotic which was isolated after some time were named as penicillin [7]. S.A Waksman introduced the term antibiotic in 1942 [4]. The antibiotic research from the innovation of Fleming to our days has been a charming, stirring, continuously changing and mounting venture [8]. Many other drugs chlortetracycline, streptomycin, chloramphenicol, rifamycin, erythromycin, cephalosporin C, lincomycin, vancomycin, amphotericin, nystatin, nalidixic acid, erythromycin and daunorubicin has been discovered from microorganisms after Penicillin got isolated [9].

MECHANISM OF ANTIBIOTICS ACTION
The mechanism of antibiotics action is well understood on its molecular basis and the major targets are well identified. Antibiotics are classified on the basis of their major target of action, where they restrain bacterial growth by interrupting crucial cellular functions [10]. It is a multistep procedure that involves a number of steps starting from the physical interaction of antibiotics to its target of action and hence a series of changes involving biochemical, molecular, and structural change. The main targets of action of antibiotics are: 1) DNA replication, 2) RNA synthesis, 3) Cell wall synthesis, and 4) Protein synthesis. Major antibiotics with their target of action are summarized in Table 1.

DNA Replication
Topology of the DNA is controlled by DNA gyrase (topoisomerase). This reaction has a significant value in DNA and mRNA synthesis. Quinolone (Ciprofloxacin, Levofloxacin, Norfloxacin) makes a complex with topoisomerase that is called the complexquinolone topoisomerase-DNA, it prevents the DNA replication by interrupting the DNA cleavage that leads towards the bacterial death [11].

Synthesis of RNA
The transcription process is mediated by RNA polymerase, in other words gene expression in prokaryotes is controlled by RNA polymerase as a main regulator in the process of transcription. So, this process is a striking target for antibiotics. Rifamycin is the common example of antibiotics which inhibits RNA synthesis [12].

Cell Wall Synthesis
Peptidoglycan is the main component of the bacterial cell wall which helps the cell to maintain its integrity in diverse environments for survival. The peptidoglycan synthesis occurs in three steps, the first step is synthesis of low molecular weight precursors in cytosol, in second step membrane-bound enzymes catalyze cell wall synthesis, the third step is the attractive target for antibiotics by acting on transpetidades and preventing the β-lactams and polymerization of the glycan synthesis of cell wall enzymes [13].

Protein Synthesis
Initiation, elongation, and termination are three steps in which mRNA translation occurs. Ribosomes are the main component of cell where translation occurs. The main target of the antibiotics are ribosomal subunits which are 30S and 50S. Macrolides block the 50S subunit, tetracycline has the affinity for 30S, tetracyclines are very active molecule that have well defined target especially against bacteria, spectinomycin acts on peptidyl-tRNA and disturb its stability by binding to the ribosomes, 16S rRNA of 30S ribosome is the target of action for kanamycin, gentamicin and streptomycin [14].

Cytoplasmic Membrane
The cytoplasmic membrane is a semi permeable membrane which allows the selective diffusion of molecules through it. Daptomycin disturbs the potassium balance by being inserted in the cytoplasmic membrane and forming ion channels which results in the intracellular potassium release. Disruption of the membrane can be caused by several antibiotics. Polymyxins are the best example of such types of antibiotics which cause the disruption of cytoplasmic membrane but they are not widely used because they produce renal and nervous toxicity [11,12,13]. Another antibiotic with different mechanism of action, that disrupts the cytoplasmic membrane synthesis by interfering the fatty acids production through inhibition of beta-ketoacyl synthases I/II (FabF / B), was launched by Merck in 2006 [15].

Antibiotic production by soil bacteria
A number of soil bacteria have the ability to produce antibiotcs [16]. Many kinds of antibiotic are produced by Bacillus species which contribute to broad range antimicrobial activity. For example Bacillus licheniformis produce bacitracin which is active against many Gram positive organisms, anaerobic cocci, Cornyebacter and Clostridia but not against other Gram negative bacteria [17]. Bacillus brevis produce gramicidin which inhibits phosphate group ATPase [16]. Streptomyces is the largest genus and it is very important medically because of its ability to produce a vast variety of antibiotics. Stanley Waksman's discovery of streptomycin was of significant importance because it efficiently combats tuberculosis and he got the Nobel Prize in 1952. Streptomycetes produce about two thirds of the antimicrobial agent which are used in human and as well as veterinary medicine. Amphoteracin B, neomycin, nystatin, erythromycin, chloramphenicol and tetracycline are some common antibiotics which are produced by Streptomycetes [18]. Many kind of antibiotic is also produced by Lactobacillus species. Nicin is one of the antibiotics produced by Lactobacillus lactis and it shows a full range of antimicrobial activity against many gram positive bacteria [19].

Antibiotics resistance and need of novel antibiotic
Even though a number of antibiotics have been discovered with the help of advance technology but still infectious diseases are the second leading causes of death worldwide affecting mainly the elderly and children. Bacterial infections are the causes of death of approximately 17 million annually [20]. The main cause of failure of available antibiotics to treat infectious disease is the rapid development of resistance to the antibiotics [21]. Antimicrobial resistance (AMR) is one of the biggest threats to human health according to the World Health Organization (WHO). The important factor which contributes to the antibiotics resistance is overuse of antibiotics and self-medication, thus emphasizing the continuous need for screening and development for new antibiotics [22]. Until recently, terrestrial microorganisms were the major source of antimicrobial compounds, however from the last two decades importance of this source has decreased because of discovery of clinically unexpected metabolites as in the case of actinomycetes [9]. Recently new metabolites discovery rate from terrestrial actinomycetes has decreased while the reisolation of known compounds has increased [23]. Thus, it is crucial to pursue discovery of new antibiotics from unexplored or underexploited habitats. For more than two decades, marine environment has become the point of focus as enduring pursuit for discovery of new drugs [24].

Importance of microbes from marine environment
The 70% of Earth's surface is covered by the ocean that is an enormous pool of natural wealth. Still, the degree of oceanic biodiversity, particularly of microbes, is scarcely known [25].
Marine bacteria can be defined as bacteria which need sea water and specially sodium for their growth [26]. The secondary metabolites produced by marine organisms have more novel and unique structures in comparison with terrestrial organisms. It is due to their adaptation to the complex living circumstance and diversity of species, and the bioactivities are much stronger [27]. In addition, along with the deep studies of marine natural products biosynthesis, some substantiation indicates that many bioactive compounds formerly originate in marine animals and plants were in fact produced or metabolized by related microorganisms [28,29,30]. Antibiotic producing bacteria are distributed throughout the marine environment like deep sea [31], aquaculture system [32], sea ice [33,34].
An attempt was made to collect the data of most of the bacterial strains isolated from marine environment by researchers from different countries from 2000 to 2013 in were isolated respectively with antimicrobial activity. In 2013 research was carried out in Korea, Iran, Malaysia & India and marine microbes belong to different species were isolated with high antimicrobial activity. Some of marine isolated with their antimicrobial activity in term of inhibition zone (mm) against common pathogenic bacteria are shown in the Table 3. For convenience their antifungal activity is not shown.
Most of the strains which were isolated from marine environment with antimicrobial activity were tested against the most common pathogenic bacteria MRSA (methicillin resistant Staphylococcus aureus). These bacterial strains showed different zone of inhibition as mentioned in table. MMG-28 showed the maximum zone of inhibition 22mm isolated from India while FStm2 and SCtm12 isolated from Malaysia showed minimum zone of inhibition 10 mm. MN38 showed maximum zone of inhibition 27mm, PRps9 with minimum zone of inhibition 8mm when these bacterial strains were tested against Bacillus subtillis.

CONCULSION
Most of the natural antibiotics available are derived from terrestrial microbes. Microbial resistance against them intensifies the need of new bacterial strain with novel antibiotic production. In this study bacterial strain isolated from marine sources were found to be promising antibiotic producing agents that can be further use to control the spreading of antibiotic resistant pathogens, which cause life threatening infections. This study also highlighted the role of other sources apart from soil community in screening of potential candidates that might be helpful for the discovery of new antibiotics.