The development of new antimicrobial agents

The past 50 years have shown how successful the pharmaceutical industry has been in developing antimicrobial agents. Until the 1980s a steady stream of new agents (or at least older modified agents) had become available. The 1980s saw little investment in new antibacterials,¹ but now this is changing. There is a need for new agents. The knowledge obtained from bacterial genetics, along with improvements in biotechnology, has given the impetus to the search for new compounds, as an understanding of the genome allows new targets to be identified. Vaccine development also holds promise for the treatment and prevention of common diseases. Group B meningococcal vaccines and HIV vaccines are currently under study but not expected in the near future.

The key development strategies fall into three groups—new modifications of existing agents, genomic approaches, and vaccine development.

Modifications of existing agents

Antimicrobial agents with ever broader spectrums of activity have been developed, and there will be an extension to the antibacterial spectrum of current compounds. Recently, fluoroquinolones have appeared and are soon to be marketed (such as trovafloxacin which is active against anaerobic bacteria²) or will be available in 2-3 years (such as SmithKline Beecham’s SB265805, which has enhanced activity against Gram positive bacteria³). The β lactam structure has been such a fruitful source of compounds in the past with the penicillins, cephalosporins, and carbapenems (among others) being so useful. Future modification of such drugs seems unlikely, although there is interest in multicyclic structures with broad spectrum activity and resistance to the novel β lactamases that Gram negative bacilli elaborate and hence are becoming increasingly resistant to.⁴ β lactamase inhibitors (such as clavulanic acid) with enhanced activity against a wider range of these hydrolysing enzymes may be developed.

A recent development is the re-evaluation of groups of pre-existing compounds. Among the orthosomycins, avilamycin has been widely used in agriculture as a growth promoter for animals. Currently under development for human use is a closely related group, the everninomycins, with activity against staphylococci, enterococci, and streptococci (pathogens that are increasingly resistant to currently available agents) including strains that may be resistant to more commonly used compounds such as vancomycin.

Potential futures

• Extension of the antibacterial spectrum of existing agents—for example, fluoroquinolones with high activity against anaerobes and streptococci

• Re-evaluation of older agents—for example, everninomycins and oxazolidinones with activity against staphylococcus, streptococcus, and enterococci

• Peptides with broad antibacterial spectrum

• Vaccines for meningococcal, pneumococcal, and viral diseases

Another group of compounds that has been used mainly by the veterinary profession is the streptogramins: virginiamycin is used as a growth promoter in poultry and pigs. In some European countries similar compounds have been used to treat infections caused by Gram positive cocci. A mixture of two streptogramins, quinupristin and dalfopristin (Synercid), is now licensed in several countries for pneumococcal disease and infections caused by other Gram positive bacteria (such as enterococci). These animal growth promoters may enhance resistance to human pathogens.⁵ Enterococci (which could cause disease in humans) have been found to be resistant to Synercid in animals treated with virginiamycin.

The oxazolidinones are another group of compounds with an antibacterial spectrum similar to the groups already mentioned. One compound, linezolid, is undergoing clinical trials for treating disease caused by multiply resistant Staphylococcus aureus and other Gram positive cocci. Linezolid inhibits protein synthesis, blocking the initiation phase of translation.

One fascinating mechanism of resistance shown by many bacteria is drug efflux—that is, the cell pumps out an antibacterial as rapidly as it enters. There is research on efflux pump inhibitors as adjuvant to antimicrobial agents.⁶

Genome approaches

The complete genomic sequencing of a number of bacterial species has been undertaken, making possible a systematic approach to the identification of novel bacterial targets. The target may be essential either to bacterial growth or to the infectious process itself (such as mucosal adherence or toxin production). It has been conservatively estimated that for any single organisms or group of organisms there is the theoretical capacity to discover, say, 10 new classes of antimicrobial,⁷ which would double the current number of widely used antimicrobials. The ability to produce vast numbers of potentially active compounds (utilising combinatorial chemistry (figure), together with the possibility of developing assays based on oligonucleotide arrays to screen the candidate, is an area of considerable interest. The first area of application is with t-RNA synthetase.

A less structured, more serendipitous approach is being taken by some pharmaceutical companies in screening their large banks of chemicals for compounds that may show some antimicrobial activity.

t-RNA synthetases

Mupirocin, commonly used topically against Staphylococcus aureus, acts by inhibiting targets of aminoacyl t-RNA synthetases. These enzymes, of which there is one for each of the 19 amino acid building blocks, are essential for synthesis of protein in bacteria. Hence there are 19 potential targets. These targets have been identified in Staphylococcus aureus and Streptococcus pneumoniae, and several lead compounds, which are not yet in clinical trials, have been developed, some with broad spectrum antimicrobial activity.

Other initiatives

Short chain peptides that have a broad spectrum of antimicrobial action have been under study for many years. These chemicals are produced by a wide range of animals as defence mechanisms. Some of the earlier agents were isolated from the skin of frogs, others from insects and pigs. They act by damaging the bacterial cell membrane, but unfortunately some can damage mammalian cells because it is difficult to target the drug to the site of infection. One, a magainin, is currently under clinical trial as a topical agent for a broad range of skin infections.⁸

Targeting is similarly a problem for antisense agents. These short chain oligonucleotide analogues of the α helix of the DNA molecule might have a role in inhibiting an important bacterial gene, possibly one involved in β lactamase production in the bacterium, by stopping transcription; however, few advances have yet come to light.

Bacteria can “communicate” at certain critical concentrations, in a way analogous to the communication elicited by pheromones. This is known as quorum sensing. Interference with the sophisticated control of this process holds some distant promise in “switching off” virulence genes in some bacteria, particularly Pseudomonas aeruginosa.⁹

Treating bacteria with a photosensitive compound which when illuminated produces a highly active radical, which can then damage the bacterial cell (photodynamic therapy) is a concept borrowed from oncology.¹⁰ The problems revolve around the need to deliver the light source to the site of infection.

Vaccines

The possibility of developing vaccines for diseases in which resistance is an increasing problem deserves more attention. A good example would be the development of a vaccine against clones of pneumococci that are resistant to penicillin. Although this may be accompanied by enhanced selection pressure and the rapid emergence of new antibiotic resistant clones not covered by the vaccine, the concept is worthy of debate.

A vaccine directed against the common group B meningococcus is certainly required. The poor immunogenicity of this polysaccharide, and potential cross reaction with tissue components, are of concern. Research has turned towards other bacterial cell components, which show some promise.

Other common bacterial diseases worth investigating are gonorrhoea, Helicobacter pylori, and enteric infections. The large array of pathogens encountered in nosocomial infections probably precludes a vaccine approach to treatment.

Conclusion

New compounds active against Gram positive cocci will probably be marketed in the next few years. More broad spectrum compounds and the products of genomic research will take longer to develop. The concern expressed in the House of Lords report¹ of a gap between need and availability may well be only too real in the coming decade.

Figure.

Combinatorial chemistry is the manufacturer of large numbers of chemicals from simple building blocks