Overcoming problems of poor drug penetration into bacteria: challenges and strategies for medicinal chemists

ABSTRACT

Introduction: Bacterial cell walls and membranes provide essential protection for bacteria against environmental influences. Different bacteria possess different cell envelopes and understanding each of these structures is crucial for the design of effective antibacterial drugs whose targets are intracellular. Optimal properties of drugs that are required for their entry into bacteria are still hard to predict. The guidelines that are suitable and well established for the penetration of a drug into eukaryotic cells are poorly adaptable to the complex world of pathogens.

Areas covered: The factors that govern the penetration of anti-infection drugs into bacteria are examined and the available strategies to overcome this therapeutically very important barrier are reviewed. The areas covered include optimization of the physicochemical properties of compounds, utilization of iron-chelating compounds, i.e. siderophores, the use of efflux pump inhibitors, and of carriers such as liposomes.

Expert opinion: Although several rules governing permeation have recently been proposed for effective antibacterial drugs, none of them has been so far established as the ‘golden’ rule. Thus, new research is needed to find a more general approach on how to increase the concentration of antibacterial compounds in bacterial cells.

KEYWORDS:

• Antibacterial
• bacterial cell wall
• bacterial cell envelope
• drug entry
• efflux pump
• permeability
• physicochemical properties
• siderophore

Article highlights

• A common reason for the failure of antibacterial drug discovery projects is the inability of compounds to penetrate to their site of action.

• The bacterial cell envelopes represent essential protection for bacteria against the environmental influences and are particularly complex in Gram-negative bacteria.

• There are marked differences in chemical space of antibacterials with respect to non-anti-infective drugs.

• Optimal properties of drugs that are required for their entry into bacteria are hard to predict.

• Recently, some predictive rules for optimal physicochemical properties of broad spectrum antibacterials have been suggested.

• Other approaches on how to increase the concentration of antibacterial compounds in bacterial cells include utilization of siderophores, using efflux pump inhibitors or using carriers such as liposomes.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Prof. Roger Pain for proofreading the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by the Slovenian Research Agency [grant no. P1-0208] and EU H2020 ITN-ETN Project INTEGRATE [Project Reference: 642620].