Suppression of intrinsic resistance to penicillins in Staphylococcus aureus by polidocanol, a dodecyl polyethyleneoxid ether

Abstract

With polidocanol, it was possible to reduce the MIC as well as the MBC of methicillin, oxacillin, penicillin G, and ampicillin against resistant staphylococci. The strongest effects were obtained with methicillin and oxacillin. All strains tested could be resensitized to these penicillins independent of the original resistance levels. Polidocanol was not inhibitory by itself for Staphylococcus aureus. Furthermore, it did not inhibit the activity of staphylococcal ,-lactamase. This permits the conclusion that an intrinsic resistance mechanism is affected by this substance. Its action cannot be simply explained by an improved accessibility of the penicillin targets as uptake, and binding of methicillin and penicillin G in resistant cells was not changed by polidocanol. On the other hand, the lysis indpced by combinations of this substance with small amounts of a penicillin was antagonized by chloramphenicol. This suggests that autolytic enzymes are involved in the polidocanol effect and possibly in the intrinsic resistance mechanism itself. Before polidocanol can trigger lysis, the penicillin must act first in some way. As could be seen with a susceptible strain, the resulting lysis did not exceed that obtained with penicillins alone. Thus, polidocanol does not exhibit an independent lytic mechanism but obviously is able to substitute penicillins in their lytic action.Bacterial resistance to penicillins can be expressed phenotypically in different ways. The most common type of penicillin resistance is that based on the inactivation of penicillins by J-lactamases. Besides this, enzyme-independent mechanisms exist which are termed intrinsic resistance. In staphylococci, the most typical form is resistance to methicillin (and oxacillin). Although altered penicillin-binding properties were recently found in resistant staphylococci (4,5,12,13), the mechanism of methicillin resistance is still unclear. In gram-negative bacteria, intrinsic resistance is due to a permeability barrier in the outer membrane (23). A special form of penicillin insensitivity is the so-called tolerance described by Sabath et al. (27) and characterized by low MICs but high MBCs of penicillins.Many successful efforts have been made to overcome the ,-lactamase-mediated type of penicillin resistance. In contrast, it was not possible until now to influence the methicillin resistance in staphylococci.In this paper, we report on the suppression of resistance to methicillin and oxacillin in Staphylococcus aureus by polidocanol (PDO). Resistance to penicillin G and ampicillin was also affected but to a lower extent. The activity of 1-lactamase, however, was not inhibited by PDO, indicating that its action is directed against an intrinsic resistance mechanism. Lysis induced by combinations of PDO and penicillins could be inhibited by chloramphenicol (CAP).This finding points to the participation of autolytic enzymes in the PDO effect and possibly in the resistance mechanism itself.

Effect of NaCl and nafcillin on penicillin-binding protein 2a and heterogeneous expression of methicillin resistance in Staphylococcus aureus

“…519,1986). The nature of this additional factor remains to be characterized, but it may act via the autolytic pathway, as others have speculated (6,14,21,30) and as our studies suggest.…”

“…Hartman and Tomasz (14) have hypothesized that an additional factor besides PBP 2a is involved, on the basis of the observation that expression of resistance in a temperature-sensitive strain changed independently of production of PBP 2a. This additional factor may be acting via the autolytic pathway (6,14,21,30).…”

Effects of growth of methicillin-resistant and -susceptible Staphylococcus aureus in the presence of beta-lactams on peptidoglycan structure and susceptibility to lytic enzymes

“…The results parallel the autolysin susceptibilities of the PGs. The results suggest that in addition to effects on cross-linking (see below), subinhibitory concentrations of antibiotics also alter the degree of 0 acetylation of PG because this is believed to be an important determinant of the susceptibility of PG to lysozyme (5,17,22,31). Strain DU4916S PCW and PG isolated from cells incubated with chloramphenicol had dramatically decreased autolysin and lysozyme susceptibilities and increased 0 acetylation (data not shown), thus confirming the results of Johannsen et al (17) and Reinicke et al (22).…”

Methicillin-resistant staphylococci

“…This factor may act within the autolytic pathway (23,121,176). This pathway controls degradation of cell wall and may mediate beta-lactam-stimulated cell lysis; therefore, it may play a role in the phenomenon of tolerance (17,77).…”