As such, it is incredibly important to study how this bug works. It is one of the most difficult organisms to work with due to a wide variety of factors. These include: slow growth rate, pathogenicity, very waxy cell walls, high levels of illegitimate recombination, and a bunch of other nuances that make the mycobacteria unique among its relatives.
One unique feature of the mycobacteria, is their unique acid-fast staining pattern. It has been shown that when treated with isoniazid (the most prescribed anti-TB drug), mycobacteria lose this pattern of staining. Therefore, one can extrapolate that their outer cell wall (filled with extremely long-chain lipids, called mycolic acids) plays an important role in both the lifestyle of M. tb. and its pathogenesis.
Two genes have been identified as having roles in mycolic acid synthesis, kasA and kasB. KasA has previously been shown to be essential (J Bacteriol. 2005 Nov;187(22):7596-606.), with kasB serving a non-essential accessory function. This paper, from Bill Jacobs’ lab at AECOM, shows that although kasB is nonessential, it is necessary for acid-fastness AND it has a large role in pathogenesis.
They first knocked out kasB using a specialized transducing phage. Knockouts of kasB had a severe deficiency in colony growth and a large change in colony morphology (Fig. below).
Also, kasB mutants lacked acid fastness and were exceptionally more sensitive to rifampicin (Fig. below).
Further biochemical analysis showed that kasB is likely involved in the production of specific mycolic acids.
However, the story gets more exciting. Immunocompetant mice that were infected with the kasB mutant, showed no signs of infection—there was no formation of granulomas and no mortality. In contrast, mice infected with wild-type died within 356 days. What is interesting to note is that although mice infected with kasB mutants did not show pathology, they still had measurable amounts of bacterial growth—indicating a persistent infection that was not able to become active (Fig. below).
The same study shows that kasB mutants act nearly identically to wild-type in mice that are immunocompromised. This means that mycolic acid production by kasB plays a role in the immune systems ability to hold M. tb. infections in check.
The authors suggest a variety of implications that their very exciting findings bring to light. For one, due to the phenotype, kasB mutants could be used specifically to study persistant infection. Secondly, kasB is clearly a candidate for deletion in an attenuated vaccine strain. Finally, and I think most importantly, this mutant shows a potential drug target for secondary drug therapy. Drugs that act on kasB or kasA could be developed in conjunction with rifampicin and isoniazid treatment.
XDR-TB cases are present in 41 countries, including the US. It is vital that we develop new lines of drugs and continue identifying drug targets. TB presents an event where scientists, public health departments, and drug industry must come together and work as a single entity. The amount of TB cases is ever increasing and I fear that the days of the sanitarium may once return to our country.
Antibiotics were invented by bacteria and fungi during thier conception in this universe. Used to control microbial niche environments, it wasn't until 1928 that Fleming (and subsequently Florey and Chain) began the widespread use of the antibiotic penicillin to control bacterial infections in humans. And so, the antibiotic revolution began.
Subsequent use (and misuse) of antibiotics has given rise to various resistant strains. These are becoming a vast problem in the treatment of diseases that once were "easily" curable, including the well-publisized MRSA and XDR-TB, as well as many others.
This paper, coming out of Harvard University, describes the isolation of bacterial strains that can live on antibiotics as their sole carbon source. Current thought states that resistance in a bacterial population occurs because of exposure in clinical settings (or a popular theme of dumping antibiotics down the drain). However, the authors show that even secluded environmental isolates have the ability to subsist on both natural and synthetic antibiotics.
Our antibiotics are just variations on themes we have seen in nature, and because of this, the environment represents a vast source of antibiotic resistance mechanisms that we have yet to discover. In niches exposed to antibiotics (ie. clinical pathogens) complete resistance is preferential. However, antibiotic metabolism (as described in this paper) would confer an advantage, even if it is only small in comparison.
I find it fascinating that in 11 different soils (urban, farm, and pristine), bacteria were present that could thrive on 18 different antibiotics as carbon sources! These bugs were not just living with the antibiotics, but were actually eating them!
We have much more to discover about antibiotic resistance mechanisms, this study clearly shows a direction that we can head to begin this task. Just as we looked to nature to develop antibioitcs, so must we look to nature to study how resistance works.
A recent graduate of the University of Pittsburgh, I have been a researcher in Graham Hatfull's lab for more than 3 years now. My primary focus has been on bacteriophage genetics and the use of phages as agents of gene transfer. However, my interests are broad in world of microbiology.
Feel free to send questions and comments to tsampson@phagehunter.org
Mycobacterium tuberculosis is the most common infectious agent in the world. Nearly 1/3 of the world population is infected, and a drastic number of these are increasingly antibiotic resistant. MDR-TB and XDR-TB are becoming more commonplace everyday, especially in regions that are combating HIV infections.
The same study shows that kasB mutants act nearly identically to wild-type in mice that are immunocompromised. This means that mycolic acid production by kasB plays a role in the immune systems ability to hold M. tb. infections in check.
