[SunilNagpal]

Many diseases (if not all) are a direct consequence of infection by some pathogenic organism (especially bacteria). Having read and known the very efficient and complicated immune systems of human beings; and especially having read about the existence of various broad-spectrum antibiotics, one must be curious to know the mechanism by which certain (most these days) bacteria become superbugs/multi-drug resistant/host immune invaders? This article is aimed at addressing most of these questions.

Mechanism(s) of Host Immune Resistance:

For any microbe to infect human body, it has to encounter and overcome upto 3 levels of human immune defense: (i). Surface Barriers (Skin, Mucus, Enzymes) which forbid the attachment of the microbe to the host (ii) Once the surface barriers are overcome, Non-Specific Resistance (innate immunity of humans) which offers resistance to all foreign microbes/antigens irrespective of their nature. It is contributed by complement system, cytokines, anti-body complexes and WBCs etc. (iii). If somehow, a bacteria penetrates the innate immunity too, it's confronted with 3rd level (or second line of defence, after surface barriers) called Specific Resistance (or Acquired Immunity). It is contributed by Memory T/B cells and antibodies produced in response to the specific bacteria/antigen.

Considering such a concerted immune system, it's quite intriguing to know the ways by which bacteria penetrate such defense measures. Following is a brief on the same:
Though the entry is possible through respiratory/food/blood route, where the 1st level cannot do much if the microbial load is very high, it comes to the role of 1st Line and 2nd Line of Defense to decide the fate.

Complement Evasion:
Presence of capsulated cell wall/membrane is the most common way of evading complement response. For e.g Neisseria gonorrhoeae has the capability to generate modified surface lipopolysaccharides to prevent MAC (membrane attack complex) formation.

Phagocytosis Evasion

Formation of a mucous layer on the surface by bacteria helps them evade contact by phagocytes (contact with the antigen/bacteria is crucial for phagocytosis), thus evading the elimination. For e.g Haemophilus influenzae does so the same way.

Some bacteria can even produce leukocidins (phagocyte killing agents). For e.g Staphylococcus sp. does so the same way.

Even there are some which can rather survive inside the phagocytes! Mycobacterium tuberculosis, Listeria monocytogenes, Rickettsia.

Specific Immune Response Evasion

Again, generation of non-antigenic capsules (like Streptococcus pyogenes), or some smart moves like genetic variations in pili so that antibodies don't get specific (like Neisseria gonorrhoeae) or production of proteases that can lyse the antibodies! (like synthesis of IgA proteases by Neisseria gonorrhoeae) etc are some of the common ways of evading specific immune response.

Mechanism(s) of Antimicrobial Resistance

Emergence of MDR Strains (Multi-drug-resistant) starins of various pathogenic bacteria is quite common these days. Here's a look at what systems they develop to evade various broad-spectrum antibiotics:

(i). Inhibition of Drug Penetration

Development of special envelopes that are impermeable to drugs is one of common mechanisms of drug resistance. E.g Mycobacteria have high content of mycolic acids in the lipid layer of peptidoglycan (cell wall) which makes it impermeable to most drugs.

(ii). Efflux Pumps
Another mode of drug resistance is development of efflux pumps in the plasma membrane that can pump the drug out of the cell even if it enters successfully! E.g Mycobacterium smegmatis, Staphylococcus aureus etc

(iii). Chemical Modification
Another mechanism recently found is of inactivating the drug by chemically modifying it's structure! Phosphorylation, glycosylation, acetylation of drugs can render them inactivated. For. eg most penicillin resistant bacteria synthesize penicillinase to hydrolyse beta-lactum ring of penicillins, making them inactive.

(iv). Alternative routes

Some drugs target a product synthesis route in bacteria and inhibit their development. Such bacteria develop resistance by either switching to pre-formed product in the surrounding/host or by increasing the rate of production. For. e.g sulfonamides inhibit folic acid synthesis in bacteria, and they develop resistance by simply using host folic acid!

So, nowadays, bacteria are becoming broad-spectrum in the mechanisms of inhibiting the affect of drugs/host immune system. This is indeed alarming, and needs concerted efforts of researchers across the world to de-code the mode of evasion, rather than just focusing on discovering new forms of anti-biotics.

Hope this article gave an insight to the aspects targeted.

Suggested Reading(s):

http://crohn.ie/archive/primer/imunevad.htm

Prescott's Microbiology (5th edition)

Thanks!