Mechanisms of antibiotic resistance

Many different bioehemieal mechanisms of antibiotic resistance have been deseribed. 

Fig. 1 Mechanisms of antibiotic resistance acquisition (a) and spreading in a community over time (b). Arrows indicate horizontal gene transfer processes and R acquired antibiotic resistance gene...

An additional mechanism of antibiotic resistance involves an alteration of PBPs. Resistant bacteria, usually gram-positive organisms, produce PBPs with low affinity for p-lactam antibiotics. The development of mutations of bacterial PBPs is involved in the mechanism for p-lactam resistance in Streptococcus pneumoniae. Enterococcus faecium, and methicillin-resistant S. aureus (MRS A). 

Mechanisms of Antibiotic Resistance Resistance to antibiotics within microorganisms occurs primarily through three different mechanisms, that is ... 

Inhibition of enzymatic inactivation Enzymatic inactivation of 3-lactam antibiotics is a major mechanism of antibiotic resistance. Inhibition of 3-lactamase by 3-lactamase inhibitor drugs (eg, sulbactam) results in synergism. 

Hermann JC, C Hensen, L Ridder, AJ Mulholland, H-D Holtje (2005) Mechanisms of antibiotic resistance QM/MM modeling of the acylation reaction of a class A beta-lactamase with benzylpeni-cillin. J. Am. Chem. Soc. 127 (12) 44544465... 

Hermann JC, L Ridder, H-D Holtje, AJ Mulholland (2006) Molecular mechanisms of antibiotic resistance QM/MM modelling of deacylation in a class A beta-lactamase. Organic Biomolecular Chemistry 4 (2) 206-210... 

Chopra, I. 1998. Overexpression of target genes as a mechanism of antibiotic resistance in bacteria. J. Antimicrob. Chemother. 41, 584—588. 

For many antibiotics, the mechanism of antibiotic resistance can help establish the mechanism of action. Therefore, it may be instructive to determine the mechanism(s) of daptomycin resistance to see if it yields insights into the mechanism of action. The incidence of reduced susceptibility to daptomycin in clinical isolates is very low and resistant strains are usually associated with deep-seated infections in compromised patients.2,9,36,37... 

One of the most potent and physiologically irreversible mechanisms of antibiotic resistance is via chemical destruction of the antibiotic warhead or scaffold. This destruction can occur through several mechanisms, but hydrolytic approaches predominate (Fig. 4). Resistance to the highly important fS-lactam antibiotics by fi-lactamases is the archetype of this class. The fS-lactams include the natural product penicifhn and cephalos... 

One of the most straightforward mechanisms of antibiotic resistance is mutation of the target to a form that has less affinity for the antibiotic. Spontaneous mutations that provide some benefit to the organism occur roughly 2 x 10 per replication (reviewed in Reference 73). Exposure to certain classes of antibiotics such as the rifamycins and fluoroquinolones can induce mutation, increasing the opportunity of developing resistance (74). Point mutations are associated with resistance to virtually all antibiotics, but this form of resistance is particularly important in the clinic for the fluoroquinolones, rifamycins such as rifampin, trimethroprim, and the sulfonamides. 

Enzyme-mediated target modification can also be an important mechanism of antibiotic resistance. The Erm proteins are... 

Just as the excision of temperate viral DNA from the host chromosome could be inaccurate, and lead to additions and deletions from the sequence, so too can the F-factor gather chromosomal DNA as the host cells change from Hfr to F+. In such instances the plasmid that is formed will transfer not only itself but also this additional DNA into recipient cells. This is particularly significant because the unassociated plasmid can replicate autonomously from the chromosome to achieve a high copy number. It can also be transferred simultaneously to many recipient bacteria. If the transported DNA encoded a mechanism of antibiotic resistance (Chapter 13) it would not be difficult to imagine how whole populations could rapidly acquire the resistance characteristics. 

Area, P, Rico, M., Brana, A.E, Villar, C.J., Hardisson, C., and Suarez, J.E., Formation of an adduct between fosfomycin and glutathione. A new mechanism of antibiotic resistance in bacteria, Antimicrob. Agents Chemother, 32, 1552, 1988. 

Shahriar Mobashery received his undergraduate (1981) and doctoral (1985) degrees from the University of Southern California and University of Chicago, respectively. Subsequent to postdoctoral research (1986-88) at the Rockefeller University, he joined the faculty at Wayne State University in 1989. Mobashery and his research group relocated to the University of Notre Dame in 2003, where he holds the position of Navari Family Professor of Life Sciences in the Department of Chemistry and Biochemistry. He was awarded the 2008 Astellas USA Foundation Award for his research on the mechanisms of antibiotic resistance, antibiotic design, and the structure of the bacterial cell wall. 

A final example demonstrating the importance of membrane permeability as a mechanism of antibiotic resistance is a study from 2006 which investigated the response of outer membrane proteins in E. coli to tetracycline and ampicilUn (Xu et al. 2006). Three known and six new outer membrane proteins related to antibiotic resistance inE. coli K-12 could be identified. 

De E, Basle A, Jaquinod M, Saint N, Mallea M, Molle G, Pagds JM. A new mechanism of antibiotic resistance in Enterobacteriaceae induced by a structural modification of the major porin. Mol Microbiol. 2001 41 189-98. 

Stewart PS. Mechanisms of antibiotic resistance in bacterial biofilms. Int J Med Microbiol 2002 292 107-13. 

---