Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification

Introduction.Macrolide, lincosamide, and streptogramin (MLS) antibiotics are chemically distinct but have a similar mode of action.They have a narrow spectrum of activity that includes gram-positive cocci (in particular, staphylo- cocci, streptococci, and enterococci) and bacilli and gram- negative cocci.These drugs, especially clindamycin, are also potent against anaerobic bacteria.Gram-negative bacilli are usually resistant to MLS antibiotics, but certain enteric bacilli and Haemophilus spp.are susceptible to azithromy- cin in vitro.However, the activities of these antibiotics against Campylobacter, Legionella, and Chlamydia spp.are at the origin of the recent renaissance of erythromycin.Macrolides are composed of a minimum of two amino and/or neutral sugars attached to a lactone ring of variable size.Macrolides commercially available or in clinical devel- opment can be divided into 14-, 15-, and 16-membered lactone ring macrolides.These classes differ in their phar- macokinetic properties and in their responses to bacterial resistance mechanisms.Lincosamides (lincomycin and the more active semisynthetic derivative clindamycin) are alkyl derivatives of proline and are devoid of a lactone ring.Streptogramin antibiotics are used in clinical practice in certain countries, including Belgium and France.They are composed of two factors, A and B (II and I in pristinamycin and M and S in virginiamycin, respectively), that act in synergy and are produced by the same microorganism.In 1956, a few years after the introduction of erythromycin in therapy, resistance of staphylococci to this drug emerged and subsequently spread in France, the United Kingdom, and the United States (13,22,37).The MLS cross-resistance phenotype due to modification of the drug target is widely distributed and has, since then, been detected in Staphylo- coccus spp.(41, 72), Streptococcus spp.(18, 23, 30), Entero- coccus spp.(16), Corynebacterium diptheriae (17), Bacteroides spp.(61, 65), Clostridium spp.(64, 79), Bacillus spp.(47, 48), Lactobacillus spp.(5, 57), Mycoplasma pneumoniae (69), Campylobacter spp.(11) and, recently, Propionibacte- rium spp.(20) and members of the family Enterobac- teriaceae (1).This paper reviews the biochemical mechanism and the genetic basis of resistance to MLS antibiotics in human pathogens by target modification.Biochemical mechanism.Clinical isolates resistant to erythromycin synthesize an enzyme that N6 dimethylates an adenine residue in 23S rRNA (40).The precise site of