Increasing bacterial resistance to virtually all available
antibiotics causes an urgent need for new antimicrobial drugs,
drug targets and therapeutic concepts. This review focuses on strategies to render bacteria highly susceptible to the antimicrobial arsenal of the immune system by targeting bacterial immune escape mechanisms that are conserved in a major number of pathogens. Virtually all innate molecules that inactivate bacteria, ranging from
antimicrobial peptides such as
defensins and
cathelicidins to bacteriolytic
enzymes such as
lysozyme and
group IIA phospholipase A2, are highly cationic in order to facilitate binding to the anionic bacterial cell envelopes. Bacteria have found ways to modulate their anionic cell wall
polymers such as
peptidoglycan,
lipopolysaccharide, teichoic
acid or
phospholipids by introducing positively charged groups. Two of these mechanisms involving the transfer of D-
alanine into
teichoic acids and of
L-lysine into
phospholipids, respectively, have been identified and characterized in Staphylococcus aureus, a major human pathogen in community- and hospital-acquired
infections. Inactivation of the responsible genes, dltABCD for alanylation of
teichoic acids and mprF for lysinylation of
phosphatidylglycerol, renders S. aureus highly susceptible to many human antimicrobial molecules and leads to profoundly attenuated virulence in several animal models. dltABCD- and mprF-related genes are found in the genomes of many bacterial pathogens indicating that the escape from human host defenses by modulation of the cell envelope is a general trait in pathogenic bacteria. This review suggests that inhibitors of DltABCD or MprF should have great potential in complementing or replacing the conventional
antibiotic therapies.