Chest
Effects of Subinhibitory Concentrations of Macrolide Antibiotics on Pseudomonas aeruginosa
Section snippets
Initiating Infection: Adhesin-Receptor Interaction
The type IV pili of P aeruginosa are polar, polymer filaments composed of a single protein subunit, PilA, or pilin. Pilin contains a highly conserved hydrophobic amino terminal region, which forms its helical core, and hydrophilic outer proteins with variable domains adapted to different functions. By virtue of its helical structure, pili rotation likely supplies the force needed for extension and retraction of the pilus strand. Microscopy studies by Bradley,9 Semmler et al,10 and Skerker and
Twitching Motility: An Essential Component of Virulence
Video images of piliated P aeruginosa colonies illustrate the fact that twitching motility along smooth surfaces promotes rapid colony expansion.1011 At the interstitial surface between the agar and the underlying plastic or glass of a Petri dish, a series of concentric rings develop, giving the appearance of a halo (Fig 2).10 Nonpiliated P aeruginosa variants or strains that harbor mutations in genes affecting pilus function fail to carry out twitching motility (Fig 2).10 Semmler and colleagues
Twitching Motility and Biofilm Formation
In the experiments of O'Toole and Kolter,17 phase contrast microscopy was used to visualize the edges of P aeruginosa microcolonies with intact twitching motility. They were described as irregular and as the result of functional type IV pili. In contrast, type IV pili-deficient strains demonstrated smooth-edged colonies. These investigators proposed that flagellar-mediated motility is required to bring P aeruginosa within proximity of a surface, and is necessary to overcome the repulsive forces
The Effects of Macrolides on Pilus Formation and Assembly
Two main mechanisms by which macrolides might act in P aeruginosa infections are to modify the inflammatory response to infection and by directly inhibiting the activity or production of P aeruginosa virulence determinants (eg, secreted virulence factors, motility, quorum sensing, and biofilm production). While the exact mode of action has yet to be fully elucidated, it has been postulated as secondary to binding of the 50S ribosomal subunit, which interferes with the elongation of polypeptide
The Effects of Macrolides on Biofilm Formation
We hypothesized that if macrolides interfere with cell surface assembly of type IV pili and the function of twitching motility, then these agents should affect some step in biofilm formation. We incubated P aeruginosa for variable periods of time in the presence or absence of sub-MIC levels of clarithromycin. We then applied microtiter assays to quantify biofilm formation. Unbound planktonic bacteria were first removed, and the surface-bound biofilms were stained with crystal violet to
Conclusion
A number of hypotheses have been offered to explain the antipseudomonal mechanism of activity of macrolides, including the innate structural aspects of 14-membered and 15-membered macrolides, the inhibition of protein synthesis that is known to contribute to the assembly, transport, and secretion of bacterial exoproducts, and the macrolide-mediated alterations in lipopolysaccharide and outer membrane proteins of the pathogen that facilitate macrolide entry and intracellular accumulation.
At
CME Questions
The American College of Chest Physicians designates this continuing medical education activity for 1 credit hour in category 1 of the Physician's Recognition Award of the American Medical Association. To obtain credit, please complete the question form at http://www.chestnet.org. Credit can be obtained ONLY through our online process.
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All of the following contribute to the virulence of P aeruginosa except:
- A.
Decreased production of alginate
- B.
Twiching motility
- C.
Formation of biofilms
- D.
- A.
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2021, ChemosphereCitation Excerpt :Once within the biofilm matrix, increases in gene mutations, tet(M) ARG promotion, and the overexpression of the TetA(C) efflux pump have been reported (Yang et al., 2019; Liu et al., 2020; May et al., 2009). Macrolides (e.g., erythromycin, roxithromycin, and azithromycin) have been found to alter the structure and architecture of the biofilm (Wozniak and Keyser, 2004). Bacteria found within the matrix may then overexpress macrolide efflux pumps encoded by the mef(E)/mel operon, as well as produce erm ARGs (i.e., ermA, ermB, and ermC) (Schroeder and Stephens, 2016; He et al., 2016).
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Learning objectives:
- 1.
To understand the determinants of Pseudomonas aeruginosa virulence.
- 2.
To understand the adhesin-receptor interaction as the primary step in the establishment of infection.
- 3.
To understand the importance of twitching motility for P aeruginosa colonization.
- 4.
To understand the effects of macrolides on twitching motility.
- 5.
To understand the effects of macrolides on biofilm formation.
Dr. Wozniak, Ms. Keyser, or the department(s) with which they are affiliated have received something of value (ie, any item, payment, or service valued in excess of $750.00) from Abbott Laboratories related directly or indirectly to the subject of this submission.
- 1.