Role of β-lactamases and outer membrane proteins in multiple β-lactam resistance of Enterobacter cloacae

The chromosomal β-lactamase and outer membrane proteins of Enterobacter cloacae were examined to determine their relative contributions to multiple antibiotic resistance in this organism. Mutants altered in β-lactamase expression, whether derived in the laboratory or recovered from patients treated with one of the new β-lactam antibiotics, were found to have no detectable alterations in outer membrane proteins. Derepression of β-lactamase in these mutants was associated with high-level resistance to multiple β-lactam antibiotics, while loss of inducible β-lactamase (i.e., production of basal enzyme levels only) was associated with acquisition of susceptibility to many β-lactam antibiotics, including cephalothin. In contrast, alteration in outer membrane proteins was associated with only moderate-level resistance to β-lactam antibiotics. However, this included resistance to such drugs as amdinocillin and Sch 34343, which were unaffected by derepression of β-lactamase. Resistance to chloramphenicol and tetracycline also accompanied changes in outer membrane proteins. Although the outer membrane proteins of various strains of E. cloacae were similar, there did appear to be some major strain-to-strain variations. Thus, it appears that alterations in both β-lactamase and outer membrane proteins can affect the susceptibility of E. cloacae to many antibiotics. However, alterations in β-lactamase alone are sufficient to produce high-level multiple β-lactam resistance in this organism.