Targeting the Resistance Mechanism

Instead of searching for a novel antibiotic free of cross-resistance, an alternative strategy would be to combine an existing drug with a compound that overcomes or at least reduces the resistance against that particular antibiotic. This approach is especially appealing because it would restore the power of a previously valuable class, and because it has already been clinically validated by the very successful combination of b-lactams with b-lactamase inhibitors capable of protecting the active b-lactam from its destruction by the enzyme [80]. To pursue this approach, the mode of action and, especially, the molecular nature of the resistance mecha-nism(s) have to be carefully considered. There are examples where a combination is not even needed, but structural modification of the antibiotic itself is sufficient to protect it from certain resistance mechanisms (e.g., penicillinase-resistant b-lac-tams such as methicillin, or overcoming inducible MLSB resistance by ketolides, etc.). A similar strategy aims at overcoming clinical resistance by synthesizing a drug derivative with increased potency. Although in this case the resistant bacterial isolates still show higher MIC values than susceptible strains, the power of the more active congener may be sufficient to achieve clinical success. For instance, the potency of the experimental quinolone DX-619 [26] against MRSA might be sufficient also to treat such strains as are resistant to other members of the quinolone class. Also, novel b-lactams like ceftobiprole [20] display exceptionally high affinity for the additional penicillin binding protein PBP 2a.

An interesting variation of this approach was provided by the detection of the so-called fem factors (factor essential for methicillin resistance) in staphylococci and many other gram-positive bacteria [81]. These genes, usually involved in certain steps of gram-positive cell wall synthesis [82], were originally detected by transposon mutagenesis experiments aiming to select for the loss of methicillin resistance in staphylococci without interfering with the resistance determinant (PBP 2a) itself. While some of these fem factors such as femX proved to be essential for bacterial growth and thus constitute a valid classical target per se [83], the most interesting finding was that inactivation of some fem factors such as femA led not only to complete loss of methicillin resistance, but even to hypersuscept-

1) With the exception of immunology-based strategies, because this field is too broad to cover within the limits of this chapter. For recent reviews, see, for example, Refs. [77-79].

ibility. In addition, it was demonstrated that such strains were also much more susceptible to a wide variety of unrelated drugs including antibiotics with a mode of action completely unrelated to cell-wall synthesis. The later finding that such genes were present not only in staphylococci but also in most other clinically relevant gram-positive bacteria rendered this approach even more attractive [84]. However, to date no useful inhibitor offem factors has been described.

Another strategy to be mentioned here is based on the fact that besides very compound-specific resistance mechanisms, bacteria have developed pump mechanisms as very general tools to export a wide variety of compounds including almost all antibiotic classes. In fact, overexpression of such pumps is an important resistance mechanism in many pathogens. Thus, in principle, blocking of such pumps would render bacteria much more susceptible towards antibiotics. An additional advantage of this approach is that spontaneous resistance frequencies have been shown to be much smaller if the relevant pumps are deleted. One of the major difficulties, however, is the large number of different pumps usually present in a single species. For example, at least five RND-type pumps can influence sensitivity to many antibiotics in P. aeruginosa [85]. In addition, a single bacterium very often harbors several mechanistically different pump systems, and pump variety is even wider among distinct species. In spite of these obstacles, however, the first examples of pump inhibitors with potential against gram-negative bacteria such as P. aeruginosa have been described [86], and it will be interesting to follow their fate in the future.

In spite of the attractiveness of such approaches, it should be mentioned that, as a rule, a combination therapy of antibiotic plus resistance breaker compound would be required. Therefore, a pharmacokinetic fit between those two components is another prerequisite, and is sometimes difficult to achieve. In addition, additive toxicities ofthe two components is ofconcern.

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