*5.2.2.1. Explore new places*

More than two-thirds of clinically used antibiotics come from natural products or their semi synthetic derivatives and most of them came out from soil actinomycetes. But recently re‐ searchers have shifted to underexplored ecological niches and bacterial species and found some new scaffolds. Compared to the terrestrial environment, the ocean remains an underexplored habitat with unparalleled biodiversity, leaving it the most promising place to yield new antibacterial metabolites. New antibacterial agents with novelty and/or complexity in chemical structure derived from marine bacteria have been elaborated clearly [64; 65]. Myx‐ obacteria, a untapped bacterial strain, can produce many useful natural products which have great potential to develop into antibacterial drug [66].

#### *5.2.2.2. The genomics*

By the mid-1990s, pharmaceutical companies have little enthusiasm for making improve‐ ment to the existing antibacterials. Hundreds of bacterial genomes have been completely de‐ ciphered since 1995, among which are many important human pathogens, attracting large pharmaceutical companies back into antibacterial discovery [67]. Genomics influence vari‐ ous aspects of the antibiotic development, including new drug target identification, under‐ standing the mechanism of antibiotic action, drug safety and efficacy assessment, bacterial resistance development, and so on [68]. Ecopia Biosciences was very skilled in using ge‐ nome-scanning approach and discovered the new antibiotic scaffold ECO-0501 which is highly effective against a series of Gram-positive pathogens [59; 69]. GlaxoSmithKline also used a genomics-derived, target-based approach to screen for new drugs. They examined more than 300 genes and employed 70 high-throughput screening campaigns over a period of 7 years, but unfortunately did not create a clinical used antibacterial [70].

bacterial spectrum and overcoming bacterial resistance. Although no clinically useful drugs have come out, extensive efforts have been made to test the effectiveness of EPIs across a

The Antibacterial Drug Discovery http://dx.doi.org/10.5772/52510 301

'Broader is better' is the rule of antibacterial activity spectrum. But developing the agents with a narrower spectrum may be helpful in treating some special antibiotic resistant patho‐ gens or the non-multiplying bacteria. One human squalene synthase inhibitor blocked staphyloxanthin biosynthesis in vitro, resulting in colorless bacteria which became more sensitive to killing by human blood and innate immune clearance [77]. Rifampicin is a standard antibiotic used for clearance of non-multiplying tuberculosis. Monoclonal antibod‐ ies (Mabs) have also become potential agents for narrow-spectrum antibacterial therapy. In clinical experiment C. difficile Mab combination MDX-066 and MDX-1388, which targets and neutralizes two main C. difficile toxins, can reduce the recurrence of C. difficile infec‐ tion [78; 79]. A microbiologic diagnosis should be made before using these kinds of antibiot‐ ics for therapy. Such genus-selective agents may have the benefit of leaving more of the

Bacteriophages and their fragments could kill the bacteria. They have been developed as an‐ tibacterials in humans, poultry and cattle industries, aquaculture and sewage treatment. This approach has novel mechanism of action that is completely different from current anti‐ microbials, but the problems are that quality control and standardization are difficult. Phage lysins, which are produced late in the viral infection cycle, can bind to cell wall peptidogly‐ can and rapidly induce Gram-positive bacteria lysis [80]. The sequencing of phages genomes

Other methods to find new drugs could be modulating immunity, developing monoclonal antibody for specific bacteria, designing antibacterial peptides (including antimicrobial pep‐ tides and compounds from animals and plants, the natural lipopeptides of bacteria and Fun‐

While the antibacterial resistance, especially multi-drug resistance continues to rise, what we should do is to investigate the potential mechanisms of drug resistance in bacteria and discover more effective antibacterials to deal with the terrible problems. Luckily there are several promising antibacterial drugs with novel mechanisms of action are in development and new types of targets have emerged. Also we need to be more precise in targeting the pathogens and limit the misuse of antimicrobials and other practices that accelerate the emergence of novel resistance mechanisms. The government must offer robust financial in‐ centives for antibacterial R&D, and build a sustainable model for developing and using anti‐

range of in vitro and in vivo assays, especially the compound MC-207,110 [76].

endogenous microfloraun unattacked compared with conventional antibiotics.

may identify more proteins suitable for novel antibacterials [81; 82].

*5.2.2.6. Other new methods*

gi [83; 84]), and so on.

bacterials.

**6. Conclusion and future issues**

**Bacteriophages**

#### *5.2.2.3. New targets*

It must be admitted that target-based genomic approach has not yielded satisfactory results, nevertheless, retooled target-based strategies can still play an important role in discovery process. Most antibiotic targets are limited to peptidoglycan synthesis, ribosomal protein synthesis, folate synthesis, and nucleic acid synthesis and topoisomerization. In the future we could continue to discover new antibiotics for these old targets through improvement of the existing scaffolds or even finding new scaffolds. For instance, Lipid II is a membraneanchored cell-wall precursor that is essential for bacterial cell-wall biosynthesis; it is not on‐ ly classical target for several old antibacterial classes, but is also targeted by the new antibiotics, such as lantibiotics, mannopeptimycins and ramoplanin [71]. Grouping targets by a common inhibitor scaffold rather than by function may lead to new targets; and as mentioned above, insights from outside the antibiotic arena are also important [59].
