**5.1. Extending the lifespan of existing antibacterials**

Although the emergency of antibiotic resistance seems inevitable, measures must be taken to prevent or at least delay this process. As mentioned above, many factors contribute to resist‐ ance, so we should adopt a complex approach. The most important way is to strictly control antibiotic misuse and overuse. Interestingly, the EU has implemented a comprehensive ban on the use of all antibiotics for growth promotion since 2006 [25]. And other developed countries also implement similar measures, but in many developing nations antibiotic use is relatively uncontrolled. As hospital-acquired infection is a major cause for antibiotic-resist‐ ance, strict antibiotic stewardship and policies should be adopted in the hospitals. For exam‐ ple, we can make some antibiotic policies to optimize the selection, dosing, route of administration, duration of the drug prescribed by the doctor, and limit the unintended con‐ sequences of antibiotic utilization [57].

#### **5.2. New antibacterial drug discovery**

As serious infectious diseases and multidrug resistance are emerging repeatedly, new anti‐ biotics are needed badly to combat these bacterial pathogens, but the progress of discovery seems relatively slow. Most chemical scaffolds of antibiotics used now were just introduced between the mid-1930s and the early 1960s (fig 2). There are many reasons for this. The first is scientific. We have discovered the easy-to-find antibiotics. Now we have to work harder and think more cleverly to find new drugs. Another reason is commercial. Antibiotics are used much less than other drugs and the new antibiotic are just used to treat serious bacteri‐ al infections at most of the time. So antibiotics have a poor return on investment. In 2008 only five major pharmaceutical companies still kept their Enthusiasm in antibacterial dis‐ covery. It is most important to delink research and development costs from drug pricing and the return from investment on antibacterial discovery [58]. If the government could es‐ tablish some subsidies and financial assistance schemes to compensate the cost, more drug companies will be attracted to this area.

**Figure 2.** Innovation gap between 1962 and 2000 [59].

LPS in the outer membrane of Polymyxin-resistant P. aeruginosa strains associates with re‐

This kind of resistance mechanisms is somewhat specific. Bacteria produce two kinds of targets: one is sensitive to antibiotics and the alternative one (usually an enzyme) that is resistant to inhibition of antibiotic. In ampicillin-resistant mutant Enterococcus faecium selected in vitro, bypass of the DD-transpeptidases by a novel class of peptidoglycan polymerases, the LD-transpeptidases, conveyed resistance to all β-lactams, except the

Although the emergency of antibiotic resistance seems inevitable, measures must be taken to prevent or at least delay this process. As mentioned above, many factors contribute to resist‐ ance, so we should adopt a complex approach. The most important way is to strictly control antibiotic misuse and overuse. Interestingly, the EU has implemented a comprehensive ban on the use of all antibiotics for growth promotion since 2006 [25]. And other developed countries also implement similar measures, but in many developing nations antibiotic use is relatively uncontrolled. As hospital-acquired infection is a major cause for antibiotic-resist‐ ance, strict antibiotic stewardship and policies should be adopted in the hospitals. For exam‐ ple, we can make some antibiotic policies to optimize the selection, dosing, route of administration, duration of the drug prescribed by the doctor, and limit the unintended con‐

As serious infectious diseases and multidrug resistance are emerging repeatedly, new anti‐ biotics are needed badly to combat these bacterial pathogens, but the progress of discovery seems relatively slow. Most chemical scaffolds of antibiotics used now were just introduced between the mid-1930s and the early 1960s (fig 2). There are many reasons for this. The first is scientific. We have discovered the easy-to-find antibiotics. Now we have to work harder and think more cleverly to find new drugs. Another reason is commercial. Antibiotics are used much less than other drugs and the new antibiotic are just used to treat serious bacteri‐ al infections at most of the time. So antibiotics have a poor return on investment. In 2008 only five major pharmaceutical companies still kept their Enthusiasm in antibacterial dis‐ covery. It is most important to delink research and development costs from drug pricing and the return from investment on antibacterial discovery [58]. If the government could es‐ tablish some subsidies and financial assistance schemes to compensate the cost, more drug

sistance development [54].

*4.1.2.4. Target bypass*

296 Drug Discovery

carbapenems [55; 56].

**5. What should we do?**

sequences of antibiotic utilization [57].

**5.2. New antibacterial drug discovery**

companies will be attracted to this area.

**5.1. Extending the lifespan of existing antibacterials**

Despite the current grim situation in management of resistant bacteria, some new drugs have recently been approved by the FDA or are in late stages of the pipeline (Table 1, 2) [60]. The new drugs belong to the following classes of compounds: oxazolidinones, glycopepti‐ des, ketolides, lycylcyclines, carbapenems and fluoroquinolones.


**Table 1.** New antibiotics of existing scaffolds


netic/pharmacodynamic properties. There are four generations of β-Lactam antibiotics, all of which contains a β-lactam nucleus in their molecular structures. The second generation (e.g., cephalexin and cefaclor) and third generation (e.g., cefotaxime, ceftazidime) are not sensitive to plasmid-mediated broad-spectrum β-lactamases and have less allergic reactions, com‐ pared with the first generation (penicillins) [61]. The fourth-generation cephalosporins pene‐ trate through the outer membrane of Gram-negative bacteria more easily and have low affinity for clinically important β-lactamases, so they have the advantage of killing many Gram-negative pathogens resistant to most third-generation [86]. Tigecycline is one of gly‐ cylcycline antibiotics derived from tetracycline and received approval from the US Food and Drug Administration for the treatment of skin, soft-tissue, and intra abdominal infections in 2005. Tigecycline can overcome the active efflux of drug from inside the bacterial cell and protection of ribosomes, which are two determinants of tetracycline resistance [62; 63]. But this approach is only a good short-term strategy to find new drugs, and but the benefit of these modified drugs will be offset quickly by the resistance to acquired through the hori‐ zontal acquisition or molecular evolution [9], which indicates that it is much more attractive

The Antibacterial Drug Discovery http://dx.doi.org/10.5772/52510 299

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

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

have great potential to develop into antibacterial drug [66].

to find novel chemical scaffolds.

*5.2.2. Novel scaffolds*

*5.2.2.2. The genomics*

*5.2.2.1. Explore new places*

**Table 2.** New antibiotics in development

#### *5.2.1. Tailoring existing scaffolds*

It seems that there are many ways to search for new antibacterials, but the key question is: how to search for new antibacterial drugs and where to look for them? The most convenient method is to modify the existing scaffolds to generate their derivates. All antibiotics ap‐ proved between the early 1960s and 2000 were synthetic derivatives of the old scaffolds ex‐ cept carbapenems. Chemical modifications of old scaffolds may lead to improved bactericidal activities, better resistance profiles, safety, tolerability or superior pharmacoki‐ netic/pharmacodynamic properties. There are four generations of β-Lactam antibiotics, all of which contains a β-lactam nucleus in their molecular structures. The second generation (e.g., cephalexin and cefaclor) and third generation (e.g., cefotaxime, ceftazidime) are not sensitive to plasmid-mediated broad-spectrum β-lactamases and have less allergic reactions, com‐ pared with the first generation (penicillins) [61]. The fourth-generation cephalosporins pene‐ trate through the outer membrane of Gram-negative bacteria more easily and have low affinity for clinically important β-lactamases, so they have the advantage of killing many Gram-negative pathogens resistant to most third-generation [86]. Tigecycline is one of gly‐ cylcycline antibiotics derived from tetracycline and received approval from the US Food and Drug Administration for the treatment of skin, soft-tissue, and intra abdominal infections in 2005. Tigecycline can overcome the active efflux of drug from inside the bacterial cell and protection of ribosomes, which are two determinants of tetracycline resistance [62; 63]. But this approach is only a good short-term strategy to find new drugs, and but the benefit of these modified drugs will be offset quickly by the resistance to acquired through the hori‐ zontal acquisition or molecular evolution [9], which indicates that it is much more attractive to find novel chemical scaffolds.
