How many modes of action should an antibiotic have?
Introduction
The overall lack of success in the past decade of genomic-driven, target-based antibacterial drug discovery has triggered a process of reconsidering the one gene–one target paradigm. In the initial years after the elucidation of the first bacterial genome in 1995, most antibacterial research groups in pharmaceutical industry and academia were busy in mining the plethora of novel bacterial sequence information in a search for novel targets that could potentially be exploited for the development of unprecedented, resistance-breaking antibiotic classes. Owing to the genomic nature of this approach the selected targets were almost exclusively encoded by single genes, which could conveniently be analyzed by bioinformatic methods for presence and conservation across a desired bacterial spectrum, redundancy (homologs) within a target species, and selectivity in comparison to the human genome [1••]. In the euphoria of that time, we seem to have overlooked that most successful antibiotics do not work that way and that their mechanisms of bacterial growth inhibition are far more complex than binding competitively to a single and unique enzyme target. This is especially true for systemically applied antibacterial monotherapeutics [2••]. Recent studies on the molecular mechanisms of antibiotic action have broadened our knowledge base and make clear that addressing more than one target and/or more than one binding site at a specific target is highly desirable in order to delay bacterial resistance development [2••, 3•].
The current review illustrates the characteristics of good targets and the promising concept of multiplicity of action by examples of successfully applied antibiotics. Advances with recently launched antibiotics and development compounds are highlighted, where it has been possible to break class-related resistances by establishing contacts with additional target sites, either via modifying the existing single pharmacophor or via combining two pharmacophors into a hybrid molecule.
Section snippets
Modes of action of successful antibiotics
In the light of the genomics-derived prediction that bacteria possess approximately 150 broadly conserved, essential genes [1••, 4] the actual number of targets addressed by therapeutically applied antibiotics seems on the first glance surprisingly low and amounts to approximately 15, or maximally 30, if specific indications (e.g. tuberculosis and topical application) are included [3•, 4]. It would go beyond the scope of this review to discuss the difficulties experienced with novel targets
Antibacterial polypharmacology
The term polypharmacology describes the phenomenon that a drug acts on multiple targets rather than on a single target. Antibacterial polypharmacology can in principle be achieved by several strategies. One option is to follow the classical serendipity approach and to screen for novel antibacterial lead structures in whole-cell assays either by investigating general potency in MIC-tests or by using screening formats that detect inhibitors of distinct metabolic pathways. An alternative approach
Multivalency as resistance-breaking strategy
Several companies have explored the options of implementing novel structural elements into established antibiotics to improve activities against resistant bacteria. Modeling approaches and structure-guided design have been especially helpful in this process. Indeed, several derivatives with impressive resistance-breaking properties, predominantly against Gram-positive bacteria, have recently been launched or are in later stages of development (e.g. see Table 2 and Figure 1).
Ceftobiprole and
Hybrid antibiotics in development
The idea to improve the pharmacological profile of antibiotics by covalent attachment of two different pharmacophors dates back more than 30 years ago, when the first dual-action cephalosporin was designed to overcome resistance by releasing an antibacterially active substituent upon opening of the β-lactam ring (either in the process of binding of the β-lactam to its transpeptidase targets or upon cleavage by β-lactamases) [35]. Subsequently Roche systematically investigated this approach by
Conclusions
Although the genomics and functional techniques did not directly pay off by providing the expected wealth of novel antibacterial lead candidates, they have generated a tremendous knowledgebase, which enabled us to complete a further learning cycle regarding promising antibacterial targets and the mechanisms, how antibacterial agents should inhibit these targets. It becomes increasingly clear that antibiotics that act on more than one target, or the target of which is not encoded by a single
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
We gratefully acknowledge Guido Schiffer (AiCuris, Wuppertal) for helpful discussions and critically reading the manuscript.
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