*5.2.2.6. Other new methods*

#### **Bacteriophages**

more than 300 genes and employed 70 high-throughput screening campaigns over a period

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].

rum to obviate the essentiality of FAS II enzymes in vivo [72].

Compared with the fruitless target-based genomic approach, traditional whole-cell assays are more effective in antibiotic discovery. Just because it is not necessary to worry about cell permeability of a novel scaffold in the development process if whole-cell assays are used. As most of the existing libraries have already been used to screen for antibacterial drugs, libra‐ ries with new chemical diversity are extremely important in this approach. Sometimes, look for libraries that don't belong to antibacterial development areas may be useful. In fact, most pharmaceutical companies of other therapeutic areas have invested considerable resources in synthesizing small molecule libraries [59]. Candidates with a strong hit in a whole-cell an‐ tibacterial assay should be tested in the right animal model early in development, because In vitro experiment results are not always reliable. For example, Antimicrobial drug target type II fatty acid synthesis (FASII) is reported to be essential for their efficacy against infections caused by multiresistant Gram-positive bacteria. But another study showed that Streptococ‐ cus agalactiae and S. aureus could take up sufficient unsaturated fatty acids from human se‐

Antibacterial spectrum is a major consideration when selecting a target for lead optimiza‐ tion. Permeability and target distribution determine the pectrum [73]. That is to say, the drug candidates should possess two properties at the same time: one is penetrating the cell and evading efflux pump systems, another is retaining potent activity at the molecular tar‐ gets. However, since almost all targets of the antibacterials in clinical use are present in all bacteria, the antibacterial drug spectra are determined largely by the ability of permeability. Therefore, some compounds are just Gram-positive organism-selective and have no effect against Gram-negative pathogens which have a second membrane acting as a permeability barrier [74; 75]. Efflux pump inhibitors (EPIs) have been explored for broadening the anti‐

of 7 years, but unfortunately did not create a clinical used antibacterial [70].

*5.2.2.3. New targets*

300 Drug Discovery

*5.2.2.4. Forward is back*

*5.2.2.5. Focus on spectrum*

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

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‐ gi [83; 84]), and so on.
