Download Production of b-lactamase by pathogens causing urinary tract

LITERATURE REVIEW
Review on molecular mechanisms and antibiotic resistance in Pathogens
Introduction
Urinary tract infection is one of the important causes of morbidity and mortality affecting
all age groups across the life span. Anatomically, urinary tract is divided into an upper portion
composed of kidneys, renal pelvis, and ureters and a lower portion made up of urinary bladder
and urethra. UTI may involve only the lower urinary tract or both the upper and lower tract.
Biofilms of the Gram-negative bacterium Pseudomonas aeruginosa are one of the major causes
of complicated urinary tract infections with detrimental outcome. To develop novel therapeutic
strategies the molecular adaption strategies of P.aeruginosa biofilms to the conditions of the
urinary tract were investigated thoroughly.
Molecular mechanisms and antibiotic resistance
UTI are the second most common pathogenic infections, it is known to affect
approximately 150 million people each year (Gonzalez et al, 1999). UTI may present at all ages
of men and women, Fungal and bacterial infections are common in male and female, but the risk
of UTI is much high in female because they have shorter urethra than men (Bethesda et al,
2005). E-coli is responsible for 80% of community acquired UTI and 40% health care associated
UTI. Other main uropathogens include Candida spp, Proteus mirabilis, Staphylococcus and
Klebsiella spp (Goering et al, 2008) etc. In most cases if bacterial infection is not treated they
travel to the urethra and multiply causing kidney infection and lead to many health problems.One
of the major bacterial infections seen in humans is genitourinary tuberculosis and nearly one
third of world’s population is estimated to be infected with Mycobacterium tuberculosis.(mete et
al , 2005). Urinary tract infections by P. aeruginosa are usually hospital-acquired and often
iatrogenic (Garibaldi 1993).They may be related to urinary tract catheterization (Marrie et al
1978) instrumentation or surgery, including renal transplantation (Moor 1966) P. aeruginosa is
the third most common nosocomial urinarytract pathogen after Escherichia coli and
Enterococci,and is responsible for almost 11% of all hospital-acquired urinary infections. P.
aeruginosa usually affects the urinary tract through ascending infection and adheres strongly to
bladder uro-epithelium (Daifuku and, Stamm 1986).
Production of b-lactamase by pathogens causing urinary tract infection (UTI) has been
demonstrated to increase resistance to antimicrobial agents. (Shahidul et al ,2013). UTI is one of
the most common bacterial infections in women, and one in four of these women will develop a
recurrence. Various risk factors include sexual intercourse, use of contraception, antimicrobials,
oestrogen, genetics, and the distance of the urethra from the anus are responsible for UTI in
womens. (Anna Virginia 2005).
Urinary tract infections (UTIs) are common post-renal transplant complications. During
the first month post-transplantation, bacterial septicemia due to UTIs is an important cause of
morbidity and mortality. (Abdulmalik 2013).
The increase in antibiotic resistance among uropathogens is a global problem,
uropathogens can change their physiologic features to induce resistance to antibiotic drugs
(Ronald et al, 2003).
Chronic infections caused by P. aeruginosa are mainly related to resistance to
antimicrobials and the production of certain virulence factors. Molecular analysis showed that
some of the genes required for biofilm formation and antimicrobial activity. Quorum sensing is a
bacterial intercellular communication mechanism for controlling gene expression in response to
population density (de Kievit, T. R., and B. H. Iglewski. 2000).
Through quorum sensing, bacteria respond to their population density and regulate gene
expression and cellular differentiation to optimize their physiology for a particular environmental
stimulus. (Shapiro,J.A, 1998).
The genes ppyR, pslA, pelA (biofilm formation), algD, algU, algL (alginate production),
fliC (flagella) and exoA (exotoxin A) are responsible for bacterial virulence (Abdolamir
Ghadaksaza et al, 2014).
Biofilm formation appears to be a widespread attribute of bacteria and may allow
increased survival ability under stressful conditions such as low nutrients or antimicrobial
activity (Mah& O’tool, 2001).
Biofilm is composed of water, exopolysaccharide, DNA, RNA, proteins and ions
(Whitchurch et al.,2002)
A typical high-affinity iron uptake system consists of a low-molecular-mass Fe (III)chelating compound, known as a siderophore, combined with its cognate membrane-located
receptor. Such iron acquisition systems are generally regarded as important virulence or fitness
factors.(Martinez et al, 1990).
The luxS gene is highly conserved among many species of gram-negative and grampositive bacteria and is thought to be responsible for synthesizing a universally recognized cell
signal referred to as autoinducer-2 (AI-2) (Surette et al 1998).
lasI of Pseudomonas aeruginosa directs the synthesis of an acyl-homoserine lactone
signal molecule used for P. aeruginosa intraspecies quorum signaling . Mutants in this gene were
unable to produce biofilms that progressed beyond the very early stages of biofilm development
(Davis et al. 1998)
P. aeruginosa have ability to acquire resistance, via mutations, to all antibiotics. This
problem seems likely to grow with the emergence of integrins that carry gene cassettes encoding
both carbapenemases and amikacin acetyltransferases(David et al, 2002)
The activity of PA-Fur on the promoters of iron-regulated genes involved in the
production of two siderophores, pyochelin and pyoverdin, and in the expression of exotoxin A.
The promoter region of the gene encoding exotoxin A (toxA) nor the promoters of the regAB
operon, required for toxA expression.These data indicate that iron regulation of exotoxin A
production involves additional factors which may ultimately be under the control of PA-Fur.
(Ochsner et al, 1995).However, reduced formation of the extracellular polysaccharide alginate,
typical for P. aeruginosa biofilms in lungs, indicated a different biofilm type for urinary tract
infections. The obtained quorum sensing response results in an increased production of virulence
factors like the extracellular lipase LipA and protease LasB and AprA explaining the harmful
cause of these infections. (Petra et al 2013)
The biofilm dispersal activity of D-Amino Acids may represent an effective strategy, in
combination with antimicrobials, to release bacteria from biofilms, subsequently enhancing
antimicrobial activity (Carlos et al., 2014). The expression of pfl and ldh associated with the
adaptive mechanism of pathogens which would have contributed mainly to the formation of biofilm(Manasa 2014).
Conclusion
Urinary tract infections (UTIs) are the second most common infections in both hospitalized
and community patients at all ages. The increasing multi-drug resistance reported in clinical
isolates has become a major concern in the public health area given that the lack of effective
treatment options for these infections, with the existing antibiotics, is becoming a problem. By
this study we can understand the changes in the characteristics of bacteria associated with urinary
tract infection that will help to introduce new treatment method and help to make changes in
drugs to control the urinary tract infections. Widespread use of antimicrobial agents often leads
to the selection of multi-drug resistant micro-organisms. Acquired or emerging bacterial
resistance to one or several antimicrobial agents is a global problem (Gold SG and Moellering
RC 1996). Many micro-organisms have become resistant to antimicrobial agents (Kunin ,1993).
The main mechanisms of antibiotic resistance are: mutations in target genes (such as DNA
gyrase and topoisomerase IV); over-expression of efflux pumps; changes in the cell envelope;
down regulation of membrane porins, and modified lipopolysaccharide component of the outer
cell membrane (in the case of Gram-negative bacteria). Biofilm formation is responsible for the
antibiotic resistance in many organisms. Understanding the properties of biofilm will help to
prevent UTI at its level. As the pattern of bacterial resistance is constantly changing, monitoring
of antimicrobial susceptibilities is important. It provides information on the pathogenic
organisms isolated from patients, and assists in choosing the most appropriate antimicrobial
therapy.
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